diff --git a/CHANGELOG.md b/CHANGELOG.md
index 8bd0a53c3c5..8ad52a2bbee 100644
--- a/CHANGELOG.md
+++ b/CHANGELOG.md
@@ -30,6 +30,8 @@ and this project adheres to [Semantic Versioning](https://semver.org/spec/v2.0.0
   ([#5096](https://github.com/open-telemetry/opentelemetry-python/pull/5096))
 - Add WeaverLiveCheck test util
   ([#5088](https://github.com/open-telemetry/opentelemetry-python/pull/5088))
+- Enable ruff `flake8-comprehensions` (C4) rules and fix violations across the codebase
+  ([#5107](https://github.com/open-telemetry/opentelemetry-python/pull/5107))
 
 ## Version 1.41.0/0.62b0 (2026-04-09)
 
diff --git a/codegen/opentelemetry-codegen-json/src/opentelemetry/codegen/json/generator.py b/codegen/opentelemetry-codegen-json/src/opentelemetry/codegen/json/generator.py
index acceb503ff8..3e9b31d776d 100644
--- a/codegen/opentelemetry-codegen-json/src/opentelemetry/codegen/json/generator.py
+++ b/codegen/opentelemetry-codegen-json/src/opentelemetry/codegen/json/generator.py
@@ -386,10 +386,10 @@ def _collect_imports(self, proto_file: str) -> Set[str]:
         Returns:
             Set of import statement strings
         """
-        return set(
+        return {
             "import " + self._get_module_path(dep_file)
             for dep_file in self._file_dependencies.get(proto_file, [])
-        )
+        }
 
     def _generate_enums_for_file(
         self,
diff --git a/exporter/opentelemetry-exporter-otlp-proto-grpc/src/opentelemetry/exporter/otlp/proto/grpc/exporter.py b/exporter/opentelemetry-exporter-otlp-proto-grpc/src/opentelemetry/exporter/otlp/proto/grpc/exporter.py
index 3627db70581..9116b44739d 100644
--- a/exporter/opentelemetry-exporter-otlp-proto-grpc/src/opentelemetry/exporter/otlp/proto/grpc/exporter.py
+++ b/exporter/opentelemetry-exporter-otlp-proto-grpc/src/opentelemetry/exporter/otlp/proto/grpc/exporter.py
@@ -342,7 +342,7 @@ def __init__(
         elif isinstance(self._headers, dict):
             self._headers = tuple(self._headers.items())
         if self._headers is None:
-            self._headers = tuple()
+            self._headers = ()
 
         if channel_options:
             # merge the default channel options with the one passed as parameter
diff --git a/opentelemetry-sdk/src/opentelemetry/sdk/util/__init__.py b/opentelemetry-sdk/src/opentelemetry/sdk/util/__init__.py
index 4adf4ed4599..eedb1b3915a 100644
--- a/opentelemetry-sdk/src/opentelemetry/sdk/util/__init__.py
+++ b/opentelemetry-sdk/src/opentelemetry/sdk/util/__init__.py
@@ -34,12 +34,8 @@ def get_dict_as_key(labels):
     """Converts a dict to be used as a unique key"""
     return tuple(
         sorted(
-            map(
-                lambda kv: (
-                    (kv[0], tuple(kv[1])) if isinstance(kv[1], list) else kv
-                ),
-                labels.items(),
-            )
+            (kv[0], tuple(kv[1])) if isinstance(kv[1], list) else kv
+            for kv in labels.items()
         )
     )
 
diff --git a/pyproject.toml b/pyproject.toml
index b0d89f84ca7..406139e5a44 100644
--- a/pyproject.toml
+++ b/pyproject.toml
@@ -81,6 +81,7 @@ select = [
   "F",   # pyflakes
   "E",   # pycodestyle errors
   "W",   # pycodestyle warnings
+  "C4",  # flake8-comprehensions
   "PLC", # pylint convention
   "PLE", # pylint error
   "Q",   # flake8-quotes
diff --git a/shim/opentelemetry-opentracing-shim/tests/testbed/testcase.py b/shim/opentelemetry-opentracing-shim/tests/testbed/testcase.py
index 3c16682fad3..745dd48e4c6 100644
--- a/shim/opentelemetry-opentracing-shim/tests/testbed/testcase.py
+++ b/shim/opentelemetry-opentracing-shim/tests/testbed/testcase.py
@@ -43,4 +43,4 @@ def assertIsNotChildOf(self, spanA, spanB):
         self.assertNotEqual(ctxA.span_id, ctxB.span_id)
 
     def assertNamesEqual(self, spans, names):
-        self.assertEqual(list(map(lambda x: x.name, spans)), names)
+        self.assertEqual([x.name for x in spans], names)