diff --git a/doc/source/whatsnew/v2.1.0.rst b/doc/source/whatsnew/v2.1.0.rst
index 44e091e12bfa6..cf7285f94b218 100644
--- a/doc/source/whatsnew/v2.1.0.rst
+++ b/doc/source/whatsnew/v2.1.0.rst
@@ -75,6 +75,7 @@ Copy-on-Write improvements
 
   - DataFrame.update / Series.update
   - DataFrame.fillna / Series.fillna
+  - DataFrame.replace / Series.replace
 
 .. _whatsnew_210.enhancements.enhancement2:
 
diff --git a/pandas/core/generic.py b/pandas/core/generic.py
index 9084395871675..7fe3a1a9c90a4 100644
--- a/pandas/core/generic.py
+++ b/pandas/core/generic.py
@@ -7623,6 +7623,15 @@ def replace(
             )
 
         inplace = validate_bool_kwarg(inplace, "inplace")
+        if inplace:
+            if not PYPY and using_copy_on_write():
+                if sys.getrefcount(self) <= REF_COUNT:
+                    warnings.warn(
+                        _chained_assignment_method_msg,
+                        ChainedAssignmentError,
+                        stacklevel=2,
+                    )
+
         if not is_bool(regex) and to_replace is not None:
             raise ValueError("'to_replace' must be 'None' if 'regex' is not a bool")
 
diff --git a/pandas/tests/arrays/categorical/test_replace.py b/pandas/tests/arrays/categorical/test_replace.py
index d38f0b8719de0..0611d04d36d10 100644
--- a/pandas/tests/arrays/categorical/test_replace.py
+++ b/pandas/tests/arrays/categorical/test_replace.py
@@ -68,7 +68,8 @@ def test_replace_categorical(to_replace, value, result, expected_error_msg):
             # ensure non-inplace call does not affect original
             tm.assert_categorical_equal(cat, expected)
 
-    pd.Series(cat, copy=False).replace(to_replace, value, inplace=True)
+    ser = pd.Series(cat, copy=False)
+    ser.replace(to_replace, value, inplace=True)
     tm.assert_categorical_equal(cat, expected)
 
 
diff --git a/pandas/tests/copy_view/test_replace.py b/pandas/tests/copy_view/test_replace.py
index dfb1caa4b2ffd..4e80f8ed6d42a 100644
--- a/pandas/tests/copy_view/test_replace.py
+++ b/pandas/tests/copy_view/test_replace.py
@@ -373,3 +373,16 @@ def test_replace_columnwise_no_op(using_copy_on_write):
         assert not np.shares_memory(get_array(df2, "a"), get_array(df, "a"))
     df2.iloc[0, 0] = 100
     tm.assert_frame_equal(df, df_orig)
+
+
+def test_replace_chained_assignment(using_copy_on_write):
+    df = DataFrame({"a": [1, np.nan, 2], "b": 1})
+    df_orig = df.copy()
+    if using_copy_on_write:
+        with tm.raises_chained_assignment_error():
+            df["a"].replace(1, 100, inplace=True)
+        tm.assert_frame_equal(df, df_orig)
+
+        with tm.raises_chained_assignment_error():
+            df[["a"]].replace(1, 100, inplace=True)
+        tm.assert_frame_equal(df, df_orig)