diff --git a/.librarian/generator-input/client-post-processing/storage-integration.yaml b/.librarian/generator-input/client-post-processing/storage-integration.yaml
index eb1fc8547227..4c77dbfd2807 100644
--- a/.librarian/generator-input/client-post-processing/storage-integration.yaml
+++ b/.librarian/generator-input/client-post-processing/storage-integration.yaml
@@ -603,7 +603,7 @@ replacements:
               "grpcio-status >= 1.75.1, < 2.0.0; python_version >= '3.14'",
               "proto-plus >= 1.22.3, <2.0.0; python_version < '3.13'",
               "proto-plus >= 1.25.0, <2.0.0; python_version >= '3.13'",
-              "protobuf >= 4.25.8, < 8.0.0",
+              "protobuf >= 6.33.5, < 8.0.0",
               "grpc-google-iam-v1 >= 0.14.0, <1.0.0",
           ],
           "protobuf": ["protobuf >= 3.20.2, < 7.0.0"],
@@ -656,7 +656,7 @@ replacements:
       grpcio==1.59.0
       grpcio-status==1.59.0
       proto-plus==1.22.3
-      protobuf==4.25.8
+      protobuf==6.33.5
       grpc-google-iam-v1==0.14.0
       opentelemetry-api==1.1.0
       requests==2.22.0
diff --git a/packages/bigframes/testing/constraints-3.10.txt b/packages/bigframes/testing/constraints-3.10.txt
index 0c76f1dda750..0e8e70b13d31 100644
--- a/packages/bigframes/testing/constraints-3.10.txt
+++ b/packages/bigframes/testing/constraints-3.10.txt
@@ -95,7 +95,7 @@ pluggy==1.6.0
 prompt_toolkit==3.0.52
 propcache==0.4.1
 proto-plus==1.27.1
-protobuf==4.25.8
+protobuf==6.33.5
 psygnal==0.15.1
 ptyprocess==0.7.0
 pure_eval==0.2.3
diff --git a/packages/bigframes/testing/constraints-3.11.txt b/packages/bigframes/testing/constraints-3.11.txt
index 77645780b7b0..a992843a315d 100644
--- a/packages/bigframes/testing/constraints-3.11.txt
+++ b/packages/bigframes/testing/constraints-3.11.txt
@@ -401,7 +401,7 @@ prompt_toolkit==3.0.51
 propcache==0.3.2
 prophet==1.1.7
 proto-plus==1.26.1
-protobuf==5.29.5
+protobuf==6.33.5
 psutil==5.9.5
 psycopg2==2.9.10
 psygnal==0.14.0
diff --git a/packages/google-api-core/google/api_core/_python_package_support.py b/packages/google-api-core/google/api_core/_python_package_support.py
index b8732b6a2f3d..52b8e56eec5b 100644
--- a/packages/google-api-core/google/api_core/_python_package_support.py
+++ b/packages/google-api-core/google/api_core/_python_package_support.py
@@ -37,7 +37,7 @@
 _PACKAGE_DEPENDENCY_WARNINGS = [
     DependencyConstraint(
         "google.protobuf",
-        minimum_fully_supported_version="4.25.8",
+        minimum_fully_supported_version="6.33.5",
         recommended_version="6.x",
     )
 ]
@@ -52,7 +52,7 @@
 def parse_version_to_tuple(version_string: str) -> ParsedVersion:
     """Safely converts a semantic version string to a comparable tuple of integers.
 
-    Example: "4.25.8" -> (4, 25, 8)
+    Example: "6.33.5" -> (6, 33, 5)
     Ignores non-numeric parts and handles common version formats.
 
     Args:
diff --git a/packages/google-api-core/noxfile.py b/packages/google-api-core/noxfile.py
index 0bad668a80dd..6a5e50cc3624 100644
--- a/packages/google-api-core/noxfile.py
+++ b/packages/google-api-core/noxfile.py
@@ -289,51 +289,36 @@ def default(
 
 @nox.session(python=ALL_PYTHON)
 @nox.parametrize(
-    ["install_grpc", "install_async_rest", "python_versions", "legacy_proto"],
+    ["install_grpc", "install_async_rest", "python_versions"],
     [
-        (True, False, None, None),  # Run unit tests with grpcio installed
-        (False, False, None, None),  # Run unit tests without grpcio installed
+        (True, False, None),  # Run unit tests with grpcio installed
+        (False, False, None),  # Run unit tests without grpcio installed
         (
             True,
             True,
             None,
-            None,
         ),  # Run unit tests with grpcio and async rest installed
         # TODO: Remove once we stop support for protobuf 4.x.
         (
             True,
             False,
             ["3.10", "3.11"],
-            4,
         ),  # Run proto4 tests with grpcio/grpcio-gcp installed
     ],
 )
 def unit(
-    session, install_grpc, install_async_rest, python_versions=None, legacy_proto=None
+    session, install_grpc, install_async_rest, python_versions=None
 ):
     """Run the unit test suite with the given configuration parameters.
 
     If `python_versions` is provided, the test suite only runs when the Python version (xx.yy) is
     one of the values in `python_versions`.
-
-    If `legacy_proto` is provided, this test suite will explicitly install the proto library at
-    that major version. Only a few values are supported at any one time; the intent is to test
-    deprecated but noyet abandoned versions.
     """
 
     if python_versions and session.python not in python_versions:
         session.log(f"Skipping session for Python {session.python}")
         session.skip()
 
-    match legacy_proto:
-        case 4:
-            # Pin protobuf to a 4.x version to ensure coverage for the legacy code path.
-            session.install("protobuf>=4.25.8,<5.0.0")
-        case None | False:
-            pass
-        case _:
-            assert False, f"Unknown legacy_proto: {legacy_proto}"
-
     default(
         session=session,
         install_grpc=install_grpc,
diff --git a/packages/google-api-core/testing/constraints-3.10.txt b/packages/google-api-core/testing/constraints-3.10.txt
index 4b3f2d263eef..ab0be9fecc03 100644
--- a/packages/google-api-core/testing/constraints-3.10.txt
+++ b/packages/google-api-core/testing/constraints-3.10.txt
@@ -6,7 +6,7 @@
 # e.g., if pyproject.toml has "foo >= 1.14.0, < 2.0.0dev",
 # Then this file should have foo==1.14.0
 googleapis-common-protos==1.63.2
-protobuf==5.29.6
+protobuf==6.33.5
 google-auth==2.14.1
 requests==2.33.0
 grpcio==1.41.0
diff --git a/packages/google-api-core/testing/constraints-async-rest-3.10.txt b/packages/google-api-core/testing/constraints-async-rest-3.10.txt
index f1b6af2fcd94..322fd7ef19bc 100644
--- a/packages/google-api-core/testing/constraints-async-rest-3.10.txt
+++ b/packages/google-api-core/testing/constraints-async-rest-3.10.txt
@@ -6,7 +6,7 @@
 # e.g., if pyproject.toml has "foo >= 1.14.0, < 2.0.0dev",
 # Then this file should have foo==1.14.0
 googleapis-common-protos==1.63.2
-protobuf==5.29.6
+protobuf==6.33.5
 google-auth==2.14.1
 requests==2.33.0
 grpcio==1.41.0
diff --git a/packages/google-cloud-access-context-manager/setup.py b/packages/google-cloud-access-context-manager/setup.py
index 94c032210fb2..1bf4b01b023c 100644
--- a/packages/google-cloud-access-context-manager/setup.py
+++ b/packages/google-cloud-access-context-manager/setup.py
@@ -30,7 +30,7 @@
 release_status = "Development Status :: 4 - Beta"
 dependencies = [
     "google-api-core[grpc] >= 2.11.0, <3.0.0",
-    "protobuf >= 4.25.8, < 8.0.0",
+    "protobuf >= 6.33.5, < 8.0.0",
 ]
 
 # Setup boilerplate below this line.
diff --git a/packages/google-cloud-access-context-manager/testing/constraints-3.9.txt b/packages/google-cloud-access-context-manager/testing/constraints-3.9.txt
index 2b0e26586a65..58e7ed875ec4 100644
--- a/packages/google-cloud-access-context-manager/testing/constraints-3.9.txt
+++ b/packages/google-cloud-access-context-manager/testing/constraints-3.9.txt
@@ -5,5 +5,5 @@
 #
 # e.g., if setup.py has "foo >= 1.14.0, < 2.0.0dev",
 # Then this file should have foo==1.14.0
-protobuf==4.25.8
+protobuf==6.33.5
 google-api-core==2.11.0
diff --git a/packages/google-cloud-audit-log/setup.py b/packages/google-cloud-audit-log/setup.py
index cc263435b60b..28e6c4524484 100644
--- a/packages/google-cloud-audit-log/setup.py
+++ b/packages/google-cloud-audit-log/setup.py
@@ -23,7 +23,7 @@
 version = "0.6.0"
 release_status = "Development Status :: 4 - Beta"
 dependencies = [
-    "protobuf >= 4.25.8, < 8.0.0",
+    "protobuf >= 6.33.5, < 8.0.0",
     "googleapis-common-protos >= 1.56.2, < 2.0.0",
 ]
 
diff --git a/packages/google-cloud-audit-log/testing/constraints-3.9.txt b/packages/google-cloud-audit-log/testing/constraints-3.9.txt
index 35307162417e..d11189ef6af6 100644
--- a/packages/google-cloud-audit-log/testing/constraints-3.9.txt
+++ b/packages/google-cloud-audit-log/testing/constraints-3.9.txt
@@ -31,5 +31,5 @@
 # Pin the version to the lower bound.
 # e.g., if setup.py has "google-cloud-foo >= 1.14.0, < 2.0.0dev",
 # Then this file should have google-cloud-foo==1.14.0
-protobuf==4.25.8
+protobuf==6.33.5
 googleapis-common-protos==1.63.2
diff --git a/packages/google-cloud-bigquery/testing/constraints-3.10.txt b/packages/google-cloud-bigquery/testing/constraints-3.10.txt
index 8e63363f1096..64b7d67cdc3d 100644
--- a/packages/google-cloud-bigquery/testing/constraints-3.10.txt
+++ b/packages/google-cloud-bigquery/testing/constraints-3.10.txt
@@ -24,4 +24,4 @@ opentelemetry-api==1.16.0
 opentelemetry-sdk==1.16.0
 opentelemetry-instrumentation==0.41b0
 proto-plus==1.22.3
-protobuf==4.25.8
+protobuf==6.33.5
\ No newline at end of file
diff --git a/packages/google-cloud-gke-hub/google/cloud/gkehub_v1/rbacrolebindingactuation_v1/__init__.py b/packages/google-cloud-gke-hub/google/cloud/gkehub_v1/rbacrolebindingactuation_v1/__init__.py
index a32bd1358a3a..b29b84210f7f 100644
--- a/packages/google-cloud-gke-hub/google/cloud/gkehub_v1/rbacrolebindingactuation_v1/__init__.py
+++ b/packages/google-cloud-gke-hub/google/cloud/gkehub_v1/rbacrolebindingactuation_v1/__init__.py
@@ -69,7 +69,7 @@
 
         def parse_version_to_tuple(version_string: str):
             """Safely converts a semantic version string to a comparable tuple of integers.
-            Example: "4.25.8" -> (4, 25, 8)
+            Example: "6.33.5" -> (6, 33, 5)
             Ignores non-numeric parts and handles common version formats.
             Args:
                 version_string: Version string in the format "x.y.z" or "x.y.z<suffix>"
@@ -98,8 +98,8 @@ def _get_version(dependency_name):
                 return (None, "--")
 
         _dependency_package = "google.protobuf"
-        _next_supported_version = "4.25.8"
-        _next_supported_version_tuple = (4, 25, 8)
+        _next_supported_version = "6.33.5"
+        _next_supported_version_tuple = (6, 33, 5)
         _recommendation = " (we recommend 6.x)"
         (_version_used, _version_used_string) = _get_version(_dependency_package)
         if _version_used and _version_used < _next_supported_version_tuple:
diff --git a/packages/google-cloud-logging/constraints.txt b/packages/google-cloud-logging/constraints.txt
index ea6d85e3e029..c37720ecae11 100644
--- a/packages/google-cloud-logging/constraints.txt
+++ b/packages/google-cloud-logging/constraints.txt
@@ -9,4 +9,4 @@ grpcio==1.75.1
 opentelemetry-api==1.16.0
 proto-plus==1.22.3
 proto-plus==1.25.0
-protobuf==4.25.8
\ No newline at end of file
+protobuf==6.33.5
\ No newline at end of file
diff --git a/packages/google-cloud-ndb/setup.py b/packages/google-cloud-ndb/setup.py
index 8c22f5349b16..258551bf2d11 100644
--- a/packages/google-cloud-ndb/setup.py
+++ b/packages/google-cloud-ndb/setup.py
@@ -42,7 +42,7 @@ def main():
     dependencies = [
         "google-api-core[grpc] >= 2.11.0, <3.0.0",
         "google-cloud-datastore >= 2.16.0, != 2.20.2, < 3.0.0",
-        "protobuf >= 4.25.8, < 8.0.0",
+        "protobuf >= 6.33.5, < 8.0.0",
         "pymemcache >= 2.1.0, < 5.0.0",
         "pytz >= 2022.1",
         "redis >= 3.0.0, < 8.0.0",
diff --git a/packages/google-cloud-ndb/testing/constraints-3.10.txt b/packages/google-cloud-ndb/testing/constraints-3.10.txt
index c4835683ad0a..1c249e72604a 100644
--- a/packages/google-cloud-ndb/testing/constraints-3.10.txt
+++ b/packages/google-cloud-ndb/testing/constraints-3.10.txt
@@ -7,7 +7,7 @@
 # Then this file should have foo==1.14.0
 google-cloud-datastore==2.16.0
 google-api-core==2.11.0
-protobuf==4.25.8
+protobuf==6.33.5
 pymemcache==2.1.0
 redis==3.0.0
 pytz==2022.1
diff --git a/packages/google-cloud-storage/setup.py b/packages/google-cloud-storage/setup.py
index b872eff7dbd8..7f9e00278aed 100644
--- a/packages/google-cloud-storage/setup.py
+++ b/packages/google-cloud-storage/setup.py
@@ -67,10 +67,10 @@
         "grpcio-status >= 1.75.1, < 2.0.0; python_version >= '3.14'",
         "proto-plus >= 1.22.3, <2.0.0; python_version < '3.13'",
         "proto-plus >= 1.25.0, <2.0.0; python_version >= '3.13'",
-        "protobuf >= 4.25.8, < 8.0.0",
+        "protobuf >= 6.33.5, < 8.0.0",
         "grpc-google-iam-v1 >= 0.14.0, <1.0.0",
     ],
-    "protobuf": ["protobuf >= 3.20.2, < 7.0.0"],
+    "protobuf": ["protobuf >= 6.33.5, < 8.0.0"],
     "tracing": [
         "opentelemetry-api >= 1.1.0, < 2.0.0",
     ],
diff --git a/packages/google-cloud-storage/testing/constraints-3.10.txt b/packages/google-cloud-storage/testing/constraints-3.10.txt
index e4294e2f1397..706d60854772 100644
--- a/packages/google-cloud-storage/testing/constraints-3.10.txt
+++ b/packages/google-cloud-storage/testing/constraints-3.10.txt
@@ -13,7 +13,7 @@ google-resumable-media==2.7.2
 grpcio==1.59.0
 grpcio-status==1.59.0
 proto-plus==1.22.3
-protobuf==4.25.8
+protobuf==6.33.5
 grpc-google-iam-v1==0.14.0
 opentelemetry-api==1.1.0
 requests==2.22.0
diff --git a/packages/googleapis-common-protos/noxfile.py b/packages/googleapis-common-protos/noxfile.py
index ce20cdcfcad8..d1b76b51e11b 100644
--- a/packages/googleapis-common-protos/noxfile.py
+++ b/packages/googleapis-common-protos/noxfile.py
@@ -210,30 +210,16 @@ def install_unittest_dependencies(session, *constraints):
 @nox.session(python=UNIT_TEST_PYTHON_VERSIONS)
 @nox.parametrize(
     "protobuf_implementation",
-    ["python", "upb", "cpp"],
+    ["python", "upb"],
 )
 def unit(session, protobuf_implementation):
     # Install all test dependencies, then install this package in-place.
 
-    if protobuf_implementation == "cpp" and session.python in (
-        "3.11",
-        "3.12",
-        "3.13",
-        "3.14",
-    ):
-        session.skip("cpp implementation is not supported in python 3.11+")
-
     constraints_path = str(
         CURRENT_DIRECTORY / "testing" / f"constraints-{session.python}.txt"
     )
     install_unittest_dependencies(session, "-c", constraints_path)
 
-    # TODO(https://github.com/googleapis/synthtool/issues/1976):
-    # Remove the 'cpp' implementation once support for Protobuf 3.x is dropped.
-    # The 'cpp' implementation requires Protobuf<4.
-    if protobuf_implementation == "cpp":
-        session.install("protobuf<4")
-
     # Run py.test against the unit tests.
     session.run(
         "py.test",
@@ -423,7 +409,7 @@ def docfx(session):
 @nox.session(python=DEFAULT_PYTHON_VERSION)
 @nox.parametrize(
     "protobuf_implementation",
-    ["python", "upb", "cpp"],
+    ["python", "upb"],
 )
 def prerelease_deps(session, protobuf_implementation):
     """
@@ -433,14 +419,6 @@ def prerelease_deps(session, protobuf_implementation):
     `pip install --pre <package>`.
     """
 
-    if protobuf_implementation == "cpp" and session.python in (
-        "3.11",
-        "3.12",
-        "3.13",
-        "3.14",
-    ):
-        session.skip("cpp implementation is not supported in python 3.11+")
-
     # Install all dependencies
     session.install("-e", ".")
 
diff --git a/packages/googleapis-common-protos/pyproject.toml b/packages/googleapis-common-protos/pyproject.toml
index 14201e0a91ec..5d1c2c88761c 100644
--- a/packages/googleapis-common-protos/pyproject.toml
+++ b/packages/googleapis-common-protos/pyproject.toml
@@ -40,7 +40,7 @@ classifiers = [
   "Topic :: Internet",
 ]
 dependencies = [
-  "protobuf >= 4.25.8, < 8.0.0",
+  "protobuf >= 6.33.5, < 8.0.0",
 ]
 
 [project.urls]
diff --git a/packages/googleapis-common-protos/testing/constraints-3.9-python-pubsub.txt b/packages/googleapis-common-protos/testing/constraints-3.9-python-pubsub.txt
index 15018df0b603..8829a3297edb 100644
--- a/packages/googleapis-common-protos/testing/constraints-3.9-python-pubsub.txt
+++ b/packages/googleapis-common-protos/testing/constraints-3.9-python-pubsub.txt
@@ -5,5 +5,5 @@
 #
 # e.g., if setup.py has "foo >= 1.14.0, < 2.0.0dev",
 # Then this file should have foo==1.14.0
-protobuf==4.25.8
+protobuf==6.33.5
 grpcio==1.51.3
\ No newline at end of file
diff --git a/packages/googleapis-common-protos/testing/constraints-3.9.txt b/packages/googleapis-common-protos/testing/constraints-3.9.txt
index 78e031894a05..a80820fc3265 100644
--- a/packages/googleapis-common-protos/testing/constraints-3.9.txt
+++ b/packages/googleapis-common-protos/testing/constraints-3.9.txt
@@ -5,5 +5,5 @@
 #
 # e.g., if setup.py has "foo >= 1.14.0, < 2.0.0dev",
 # Then this file should have foo==1.14.0
-protobuf==4.25.8
+protobuf==6.33.5
 grpcio==1.44.0
\ No newline at end of file
diff --git a/packages/grpc-google-iam-v1/noxfile.py b/packages/grpc-google-iam-v1/noxfile.py
index 6d0703ed100b..27ec027fa309 100644
--- a/packages/grpc-google-iam-v1/noxfile.py
+++ b/packages/grpc-google-iam-v1/noxfile.py
@@ -210,30 +210,16 @@ def install_unittest_dependencies(session, *constraints):
 @nox.session(python=UNIT_TEST_PYTHON_VERSIONS)
 @nox.parametrize(
     "protobuf_implementation",
-    ["python", "upb", "cpp"],
+    ["python", "upb"],
 )
 def unit(session, protobuf_implementation):
     # Install all test dependencies, then install this package in-place.
 
-    if protobuf_implementation == "cpp" and session.python in (
-        "3.11",
-        "3.12",
-        "3.13",
-        "3.14",
-    ):
-        session.skip("cpp implementation is not supported in python 3.11+")
-
     constraints_path = str(
         CURRENT_DIRECTORY / "testing" / f"constraints-{session.python}.txt"
     )
     install_unittest_dependencies(session, "-c", constraints_path)
 
-    # TODO(https://github.com/googleapis/synthtool/issues/1976):
-    # Remove the 'cpp' implementation once support for Protobuf 3.x is dropped.
-    # The 'cpp' implementation requires Protobuf<4.
-    if protobuf_implementation == "cpp":
-        session.install("protobuf<4")
-
     # Run py.test against the unit tests.
     session.run(
         "py.test",
@@ -423,7 +409,7 @@ def docfx(session):
 @nox.session(python=DEFAULT_PYTHON_VERSION)
 @nox.parametrize(
     "protobuf_implementation",
-    ["python", "upb", "cpp"],
+    ["python", "upb"],
 )
 def prerelease_deps(session, protobuf_implementation):
     """
@@ -433,14 +419,6 @@ def prerelease_deps(session, protobuf_implementation):
     `pip install --pre <package>`.
     """
 
-    if protobuf_implementation == "cpp" and session.python in (
-        "3.11",
-        "3.12",
-        "3.13",
-        "3.14",
-    ):
-        session.skip("cpp implementation is not supported in python 3.11+")
-
     # Install all dependencies
     session.install("-e", ".")
 
diff --git a/packages/grpc-google-iam-v1/pyproject.toml b/packages/grpc-google-iam-v1/pyproject.toml
index d9168e103f28..db219578fe32 100644
--- a/packages/grpc-google-iam-v1/pyproject.toml
+++ b/packages/grpc-google-iam-v1/pyproject.toml
@@ -42,7 +42,7 @@ classifiers = [
 dependencies = [
   "grpcio >= 1.44.0, < 2.0.0",
   "googleapis-common-protos[grpc] >= 1.63.2, < 2.0.0",
-  "protobuf >= 4.25.8, < 8.0.0",
+  "protobuf >= 6.33.5, < 8.0.0",
 ]
 
 [project.urls]
diff --git a/packages/grpc-google-iam-v1/testing/constraints-3.9-python-pubsub.txt b/packages/grpc-google-iam-v1/testing/constraints-3.9-python-pubsub.txt
index b6293bae2f4a..d283572a28e2 100644
--- a/packages/grpc-google-iam-v1/testing/constraints-3.9-python-pubsub.txt
+++ b/packages/grpc-google-iam-v1/testing/constraints-3.9-python-pubsub.txt
@@ -5,5 +5,5 @@
 #
 # e.g., if setup.py has "foo >= 1.14.0, < 2.0.0dev",
 # Then this file should have foo==1.14.0
-protobuf==4.25.8
+protobuf==6.33.5
 grpcio==1.51.3
diff --git a/packages/grpc-google-iam-v1/testing/constraints-3.9.txt b/packages/grpc-google-iam-v1/testing/constraints-3.9.txt
index 8cd2eb21f15b..b24046275cbe 100644
--- a/packages/grpc-google-iam-v1/testing/constraints-3.9.txt
+++ b/packages/grpc-google-iam-v1/testing/constraints-3.9.txt
@@ -5,5 +5,5 @@
 #
 # e.g., if setup.py has "foo >= 1.14.0, < 2.0.0dev",
 # Then this file should have foo==1.14.0
-protobuf==4.25.8
+protobuf==6.33.5
 grpcio==1.44.0
diff --git a/packages/proto-plus/noxfile.py b/packages/proto-plus/noxfile.py
index 4e07083cd49c..847092bd314d 100644
--- a/packages/proto-plus/noxfile.py
+++ b/packages/proto-plus/noxfile.py
@@ -43,20 +43,10 @@
 
 
 @nox.session(python=PYTHON_VERSIONS)
-@nox.parametrize("implementation", ["cpp", "upb", "python"])
+@nox.parametrize("implementation", ["upb", "python"])
 def unit(session, implementation):
     """Run the unit test suite."""
 
-    # TODO(https://github.com/googleapis/gapic-generator-python/issues/2388):
-    # Remove this check once support for Protobuf 3.x is dropped.
-    if implementation == "cpp" and session.python in (
-        "3.11",
-        "3.12",
-        "3.13",
-        "3.14",
-    ):
-        session.skip("cpp implementation is not supported in python 3.11+")
-
     constraints_path = str(
         CURRENT_DIRECTORY / "testing" / f"constraints-{session.python}.txt"
     )
@@ -64,11 +54,6 @@ def unit(session, implementation):
     session.env["PROTOCOL_BUFFERS_PYTHON_IMPLEMENTATION"] = implementation
     session.install("coverage", "pytest", "pytest-cov", "pytz")
     session.install("-e", ".[testing]", "-c", constraints_path)
-    # TODO(https://github.com/googleapis/proto-plus-python/issues/389):
-    # Remove the 'cpp' implementation once support for Protobuf 3.x is dropped.
-    # The 'cpp' implementation requires Protobuf<4.
-    if implementation == "cpp":
-        session.install("protobuf<4")
 
     # TODO(https://github.com/googleapis/proto-plus-python/issues/403): re-enable `-W=error`
     # The warnings-as-errors flag `-W=error` was removed in
diff --git a/packages/proto-plus/pyproject.toml b/packages/proto-plus/pyproject.toml
index efe9a2a3b2ec..f5a8cd2545c1 100644
--- a/packages/proto-plus/pyproject.toml
+++ b/packages/proto-plus/pyproject.toml
@@ -38,7 +38,7 @@ classifiers = [
   "Topic :: Software Development :: Code Generators",
   "Topic :: Software Development :: Libraries :: Python Modules",
 ]
-dependencies = ["protobuf >= 4.25.8, < 8.0.0"]
+dependencies = ["protobuf >= 6.33.5, < 8.0.0"]
 dynamic = ["version"]
 
 [project.urls]
diff --git a/packages/proto-plus/testing/constraints-3.9.txt b/packages/proto-plus/testing/constraints-3.9.txt
index 2aa3356da157..6dd4545011b5 100644
--- a/packages/proto-plus/testing/constraints-3.9.txt
+++ b/packages/proto-plus/testing/constraints-3.9.txt
@@ -6,4 +6,4 @@
 # e.g., if setup.py has "foo >= 1.14.0, < 2.0.0dev",
 # Then this file should have foo==1.14.0
 google-api-core==2.11.0
-protobuf==4.25.8
+protobuf==6.33.5
diff --git a/packages/proto-plus/tests/test_fields_enum.py b/packages/proto-plus/tests/test_fields_enum.py
index de1184b3979e..884449e60863 100644
--- a/packages/proto-plus/tests/test_fields_enum.py
+++ b/packages/proto-plus/tests/test_fields_enum.py
@@ -357,25 +357,6 @@ class Task(proto.Message):
     assert t == t2
 
 
-if os.environ.get("PROTOCOL_BUFFERS_PYTHON_IMPLEMENTATION", "python") == "cpp":
-    # This test only works, and is only relevant, with the cpp runtime.
-    # Python just doesn't give a care and lets it work anyway.
-    def test_enum_alias_bad():
-        # Certain enums may shadow the different enum monikers with the same value.
-        # This is generally discouraged, and protobuf will object by default,
-        # but will explicitly allow this behavior if the enum is defined with
-        # the `allow_alias` option set.
-        with pytest.raises(TypeError):
-            # The wrapper message is a hack to avoid manifest wrangling to
-            # define the enum.
-            class BadMessage(proto.Message):
-                class BadEnum(proto.Enum):
-                    UNKNOWN = 0
-                    DEFAULT = 0
-
-                bad_dup_enum = proto.Field(proto.ENUM, number=1, enum=BadEnum)
-
-
 def test_enum_alias_good():
     # Have to split good and bad enum alias into two tests so that the generated
     # file descriptor is properly created.