diff --git a/CHANGELOG.md b/CHANGELOG.md
index be5cd01123..f9d97a5986 100644
--- a/CHANGELOG.md
+++ b/CHANGELOG.md
@@ -21,6 +21,8 @@ and this project adheres to [Semantic Versioning](https://semver.org/spec/v2.0.0
   ([#3266](https://github.com/open-telemetry/opentelemetry-python-contrib/pull/3266))
 - `opentelemetry-instrumentation-botocore` Add support for GenAI choice events
   ([#3275](https://github.com/open-telemetry/opentelemetry-python-contrib/pull/3275))
+- `opentelemetry-instrumentation` make it simpler to initialize auto-instrumentation programmatically
+  ([#3273](https://github.com/open-telemetry/opentelemetry-python-contrib/pull/3273))
 
 ### Fixed
 
diff --git a/opentelemetry-instrumentation/README.rst b/opentelemetry-instrumentation/README.rst
index 3ed88c213f..ce17dbbe0c 100644
--- a/opentelemetry-instrumentation/README.rst
+++ b/opentelemetry-instrumentation/README.rst
@@ -130,6 +130,19 @@ start celery with the rest of the arguments.
 The above command will configure the global trace provider to use the Random IDs Generator, and then
 pass ``--port=3000`` to ``flask run``.
 
+Programmatic Auto-instrumentation
+--------------------
+
+::
+
+    from opentelemetry.instrumentation import auto_instrumentation
+    auto_instrumentation.initialize()
+
+
+If you are in an environment where you cannot use opentelemetry-instrument to inject auto-instrumentation you can do so programmatically with
+the code above. Please note that some instrumentations may require the ``initialize()`` method to be called before the library they
+instrument is imported.
+
 References
 ----------
 
diff --git a/opentelemetry-instrumentation/src/opentelemetry/instrumentation/auto_instrumentation/__init__.py b/opentelemetry-instrumentation/src/opentelemetry/instrumentation/auto_instrumentation/__init__.py
index 963b3a6956..69af0b4cea 100644
--- a/opentelemetry-instrumentation/src/opentelemetry/instrumentation/auto_instrumentation/__init__.py
+++ b/opentelemetry-instrumentation/src/opentelemetry/instrumentation/auto_instrumentation/__init__.py
@@ -19,6 +19,12 @@
 from re import sub
 from shutil import which
 
+from opentelemetry.instrumentation.auto_instrumentation._load import (
+    _load_configurators,
+    _load_distro,
+    _load_instrumentors,
+)
+from opentelemetry.instrumentation.utils import _python_path_without_directory
 from opentelemetry.instrumentation.version import __version__
 from opentelemetry.util._importlib_metadata import entry_points
 
@@ -110,3 +116,20 @@ def run() -> None:
 
     executable = which(args.command)
     execl(executable, executable, *args.command_args)
+
+
+def initialize():
+    """Setup auto-instrumentation, called by the sitecustomize module"""
+    # prevents auto-instrumentation of subprocesses if code execs another python process
+    if "PYTHONPATH" in environ:
+        environ["PYTHONPATH"] = _python_path_without_directory(
+            environ["PYTHONPATH"], dirname(abspath(__file__)), pathsep
+        )
+
+    try:
+        distro = _load_distro()
+        distro.configure()
+        _load_configurators()
+        _load_instrumentors(distro)
+    except Exception:  # pylint: disable=broad-except
+        _logger.exception("Failed to auto initialize OpenTelemetry")
diff --git a/opentelemetry-instrumentation/src/opentelemetry/instrumentation/auto_instrumentation/sitecustomize.py b/opentelemetry-instrumentation/src/opentelemetry/instrumentation/auto_instrumentation/sitecustomize.py
index 912675f1b7..c126b87372 100644
--- a/opentelemetry-instrumentation/src/opentelemetry/instrumentation/auto_instrumentation/sitecustomize.py
+++ b/opentelemetry-instrumentation/src/opentelemetry/instrumentation/auto_instrumentation/sitecustomize.py
@@ -12,33 +12,6 @@
 # See the License for the specific language governing permissions and
 # limitations under the License.
 
-from logging import getLogger
-from os import environ
-from os.path import abspath, dirname, pathsep
-
-from opentelemetry.instrumentation.auto_instrumentation._load import (
-    _load_configurators,
-    _load_distro,
-    _load_instrumentors,
-)
-from opentelemetry.instrumentation.utils import _python_path_without_directory
-
-logger = getLogger(__name__)
-
-
-def initialize():
-    # prevents auto-instrumentation of subprocesses if code execs another python process
-    environ["PYTHONPATH"] = _python_path_without_directory(
-        environ["PYTHONPATH"], dirname(abspath(__file__)), pathsep
-    )
-
-    try:
-        distro = _load_distro()
-        distro.configure()
-        _load_configurators()
-        _load_instrumentors(distro)
-    except Exception:  # pylint: disable=broad-except
-        logger.exception("Failed to auto initialize opentelemetry")
-
+from opentelemetry.instrumentation.auto_instrumentation import initialize
 
 initialize()
diff --git a/opentelemetry-instrumentation/tests/auto_instrumentation/test_initialize.py b/opentelemetry-instrumentation/tests/auto_instrumentation/test_initialize.py
new file mode 100644
index 0000000000..6d05a69c8e
--- /dev/null
+++ b/opentelemetry-instrumentation/tests/auto_instrumentation/test_initialize.py
@@ -0,0 +1,61 @@
+# Copyright The OpenTelemetry Authors
+#
+# Licensed under the Apache License, Version 2.0 (the "License");
+# you may not use this file except in compliance with the License.
+# You may obtain a copy of the License at
+#
+#     http://www.apache.org/licenses/LICENSE-2.0
+#
+# Unless required by applicable law or agreed to in writing, software
+# distributed under the License is distributed on an "AS IS" BASIS,
+# WITHOUT WARRANTIES OR CONDITIONS OF ANY KIND, either express or implied.
+# See the License for the specific language governing permissions and
+# limitations under the License.
+# type: ignore
+
+from os import environ
+from os.path import abspath, dirname, pathsep
+from unittest import TestCase
+from unittest.mock import patch
+
+from opentelemetry.instrumentation import auto_instrumentation
+
+# TODO: convert to assertNoLogs instead of mocking logger when 3.10 is baseline
+
+
+class TestInitialize(TestCase):
+    auto_instrumentation_path = dirname(abspath(auto_instrumentation.__file__))
+
+    @patch.dict("os.environ", {}, clear=True)
+    @patch("opentelemetry.instrumentation.auto_instrumentation._logger")
+    def test_handles_pythonpath_not_set(self, logger_mock):
+        auto_instrumentation.initialize()
+        self.assertNotIn("PYTHONPATH", environ)
+        logger_mock.exception.assert_not_called()
+
+    @patch.dict("os.environ", {"PYTHONPATH": "."})
+    @patch("opentelemetry.instrumentation.auto_instrumentation._logger")
+    def test_handles_pythonpath_set(self, logger_mock):
+        auto_instrumentation.initialize()
+        self.assertEqual(environ["PYTHONPATH"], ".")
+        logger_mock.exception.assert_not_called()
+
+    @patch.dict(
+        "os.environ",
+        {"PYTHONPATH": auto_instrumentation_path + pathsep + "foo"},
+    )
+    @patch("opentelemetry.instrumentation.auto_instrumentation._logger")
+    def test_clears_auto_instrumentation_path(self, logger_mock):
+        auto_instrumentation.initialize()
+        self.assertEqual(environ["PYTHONPATH"], "foo")
+        logger_mock.exception.assert_not_called()
+
+    @patch("opentelemetry.instrumentation.auto_instrumentation._logger")
+    @patch("opentelemetry.instrumentation.auto_instrumentation._load_distro")
+    def test_handles_exceptions(self, load_distro_mock, logger_mock):
+        # pylint:disable=no-self-use
+        load_distro_mock.side_effect = ValueError
+        auto_instrumentation.initialize()
+        logger_mock.exception.assert_called_once_with(
+            "Failed to auto initialize OpenTelemetry"
+        )
diff --git a/opentelemetry-instrumentation/tests/auto_instrumentation/test_sitecustomize.py b/opentelemetry-instrumentation/tests/auto_instrumentation/test_sitecustomize.py
new file mode 100644
index 0000000000..97b5133c38
--- /dev/null
+++ b/opentelemetry-instrumentation/tests/auto_instrumentation/test_sitecustomize.py
@@ -0,0 +1,28 @@
+# Copyright The OpenTelemetry Authors
+#
+# Licensed under the Apache License, Version 2.0 (the "License");
+# you may not use this file except in compliance with the License.
+# You may obtain a copy of the License at
+#
+#     http://www.apache.org/licenses/LICENSE-2.0
+#
+# Unless required by applicable law or agreed to in writing, software
+# distributed under the License is distributed on an "AS IS" BASIS,
+# WITHOUT WARRANTIES OR CONDITIONS OF ANY KIND, either express or implied.
+# See the License for the specific language governing permissions and
+# limitations under the License.
+# type: ignore
+
+from unittest import TestCase
+from unittest.mock import patch
+
+
+class TestSiteCustomize(TestCase):
+    # pylint:disable=import-outside-toplevel,unused-import,no-self-use
+    @patch("opentelemetry.instrumentation.auto_instrumentation.initialize")
+    def test_sitecustomize_side_effects(self, initialize_mock):
+        initialize_mock.assert_not_called()
+
+        import opentelemetry.instrumentation.auto_instrumentation.sitecustomize  # NOQA
+
+        initialize_mock.assert_called_once()