diff --git a/owlbot.py b/owlbot.py
index e7fb391c2a..40443971d1 100644
--- a/owlbot.py
+++ b/owlbot.py
@@ -238,8 +238,18 @@ def place_before(path, text, *before_text, escape=None):
     """@nox.session\(python=SYSTEM_TEST_PYTHON_VERSIONS\)
 def system\(session\):""",
     """@nox.session(python=SYSTEM_TEST_PYTHON_VERSIONS)
-@nox.parametrize("database_dialect", ["GOOGLE_STANDARD_SQL", "POSTGRESQL"])
-def system(session, database_dialect):""",
+@nox.parametrize(
+    "protobuf_implementation,database_dialect",
+    [
+        ("python", "GOOGLE_STANDARD_SQL"),
+        ("python", "POSTGRESQL"),
+        ("upb", "GOOGLE_STANDARD_SQL"),
+        ("upb", "POSTGRESQL"),
+        ("cpp", "GOOGLE_STANDARD_SQL"),
+        ("cpp", "POSTGRESQL"),
+    ],
+)
+def system(session, protobuf_implementation, database_dialect):""",
 )
 
 s.replace(
@@ -248,6 +258,7 @@ def system(session, database_dialect):""",
         \)""",
     """*session.posargs,
             env={
+                "PROTOCOL_BUFFERS_PYTHON_IMPLEMENTATION": protobuf_implementation,
                 "SPANNER_DATABASE_DIALECT": database_dialect,
                 "SKIP_BACKUP_TESTS": "true",
             },
@@ -345,6 +356,19 @@ def mockserver(session):
     escape="()_*:",
 )
 
+s.replace(
+    "noxfile.py",
+    "install_systemtest_dependencies\(session, \"-c\", constraints_path\)",
+    """install_systemtest_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")
+"""
+)
+
 place_before(
     "noxfile.py",
     "UNIT_TEST_PYTHON_VERSIONS: List[str] = [",
diff --git a/setup.py b/setup.py
index 6d01b265cc..a32883075b 100644
--- a/setup.py
+++ b/setup.py
@@ -36,13 +36,13 @@
     release_status = "Development Status :: 5 - Production/Stable"
 
 dependencies = [
-    "google-api-core[grpc] >= 1.34.0, <3.0.0dev,!=2.0.*,!=2.1.*,!=2.2.*,!=2.3.*,!=2.4.*,!=2.5.*,!=2.6.*,!=2.7.*,!=2.8.*,!=2.9.*,!=2.10.*",
-    "google-cloud-core >= 1.4.4, < 3.0dev",
-    "grpc-google-iam-v1 >= 0.12.4, <1.0.0dev",
-    "proto-plus >= 1.22.0, <2.0.0dev",
+    "google-api-core[grpc] >= 1.34.0, <3.0.0,!=2.0.*,!=2.1.*,!=2.2.*,!=2.3.*,!=2.4.*,!=2.5.*,!=2.6.*,!=2.7.*,!=2.8.*,!=2.9.*,!=2.10.*",
+    "google-cloud-core >= 1.4.4, < 3.0.0",
+    "grpc-google-iam-v1 >= 0.12.4, <1.0.0",
+    "proto-plus >= 1.22.0, <2.0.0",
     "sqlparse >= 0.4.4",
-    "proto-plus >= 1.22.2, <2.0.0dev; python_version>='3.11'",
-    "protobuf>=3.20.2,<6.0.0dev,!=4.21.0,!=4.21.1,!=4.21.2,!=4.21.3,!=4.21.4,!=4.21.5",
+    "proto-plus >= 1.22.2, <2.0.0; python_version>='3.11'",
+    "protobuf>=3.20.2,<7.0.0,!=4.21.0,!=4.21.1,!=4.21.2,!=4.21.3,!=4.21.4,!=4.21.5",
     "grpc-interceptor >= 0.15.4",
 ]
 extras = {