diff --git a/doc/source/whatsnew/v2.2.0.rst b/doc/source/whatsnew/v2.2.0.rst
index c35473b852eb9..9295ad6cb9aa6 100644
--- a/doc/source/whatsnew/v2.2.0.rst
+++ b/doc/source/whatsnew/v2.2.0.rst
@@ -92,7 +92,7 @@ Other API changes
 
 Deprecations
 ~~~~~~~~~~~~
--
+- Deprecated allowing non-keyword arguments in :meth:`DataFrame.to_pickle` except ``path``. (:issue:`54229`)
 -
 
 .. ---------------------------------------------------------------------------
diff --git a/pandas/core/generic.py b/pandas/core/generic.py
index 7624c8f7c7930..88fa32ca5b20b 100644
--- a/pandas/core/generic.py
+++ b/pandas/core/generic.py
@@ -3017,6 +3017,9 @@ def to_sql(
         )
 
     @final
+    @deprecate_nonkeyword_arguments(
+        version=None, allowed_args=["self", "path"], name="to_pickle"
+    )
     @doc(
         storage_options=_shared_docs["storage_options"],
         compression_options=_shared_docs["compression_options"] % "path",
diff --git a/pandas/tests/generic/test_generic.py b/pandas/tests/generic/test_generic.py
index 87beab04bc586..7b5b31037d445 100644
--- a/pandas/tests/generic/test_generic.py
+++ b/pandas/tests/generic/test_generic.py
@@ -460,3 +460,13 @@ def test_bool_dep(self) -> None:
         )
         with tm.assert_produces_warning(FutureWarning, match=msg_warn):
             DataFrame({"col": [False]}).bool()
+
+    def test_drop_pos_args_deprecation_for_to_pickle(self):
+        # GH-54229
+        df = DataFrame({"a": [1, 2, 3]})
+        msg = (
+            r"In a future version of pandas all arguments of to_pickle "
+            r"except for the argument 'path' will be keyword-only"
+        )
+        with tm.assert_produces_warning(FutureWarning, match=msg):
+            df.to_pickle("./dummy.pkl", "infer")