diff --git a/doc/source/whatsnew/v2.1.0.rst b/doc/source/whatsnew/v2.1.0.rst
index 198a7155e1a1e..1119117c411d3 100644
--- a/doc/source/whatsnew/v2.1.0.rst
+++ b/doc/source/whatsnew/v2.1.0.rst
@@ -27,6 +27,14 @@ Copy-on-Write improvements
   of those Index objects for the columns of the DataFrame (:issue:`52947`)
 - Add lazy copy mechanism to :meth:`DataFrame.eval` (:issue:`53746`)
 
+- Trying to operate inplace on a temporary column selection
+  (for example, ``df["a"].fillna(100, inplace=True)``)
+  will now always raise a warning when Copy-on-Write is enabled. In this mode,
+  operating inplace like this will never work, since the selection behaves
+  as a temporary copy. This holds true for:
+
+  - DataFrame.fillna / Series.fillna
+
 .. _whatsnew_210.enhancements.enhancement2:
 
 ``map(func, na_action="ignore")`` now works for all array types
diff --git a/pandas/core/generic.py b/pandas/core/generic.py
index f049e9d479b26..68e5fbd696ab9 100644
--- a/pandas/core/generic.py
+++ b/pandas/core/generic.py
@@ -9,6 +9,7 @@
 import operator
 import pickle
 import re
+import sys
 from typing import (
     TYPE_CHECKING,
     Any,
@@ -89,13 +90,19 @@
     WriteExcelBuffer,
     npt,
 )
+from pandas.compat import (
+    PY311,
+    PYPY,
+)
 from pandas.compat._optional import import_optional_dependency
 from pandas.compat.numpy import function as nv
 from pandas.errors import (
     AbstractMethodError,
+    ChainedAssignmentError,
     InvalidIndexError,
     SettingWithCopyError,
     SettingWithCopyWarning,
+    _chained_assignment_method_msg,
 )
 from pandas.util._decorators import doc
 from pandas.util._exceptions import find_stack_level
@@ -7083,6 +7090,16 @@ def fillna(
         Note that column D is not affected since it is not present in df2.
         """
         inplace = validate_bool_kwarg(inplace, "inplace")
+        if inplace:
+            if not PYPY and using_copy_on_write():
+                refcount = 2 if PY311 else 3
+                if sys.getrefcount(self) <= refcount:
+                    warnings.warn(
+                        _chained_assignment_method_msg,
+                        ChainedAssignmentError,
+                        stacklevel=2,
+                    )
+
         value, method = validate_fillna_kwargs(value, method)
         if method is not None:
             warnings.warn(
diff --git a/pandas/errors/__init__.py b/pandas/errors/__init__.py
index 438f504968b2d..0c5b8caeaba6e 100644
--- a/pandas/errors/__init__.py
+++ b/pandas/errors/__init__.py
@@ -393,6 +393,17 @@ class ChainedAssignmentError(Warning):
 )
 
 
+_chained_assignment_method_msg = (
+    "A value is trying to be set on a copy of a DataFrame or Series "
+    "through chained assignment.\n"
+    "When using the Copy-on-Write mode, such chained assignment never works "
+    "to update the original DataFrame or Series, because the intermediate "
+    "object on which we are setting values always behaves as a copy.\n\n"
+    "Try using 'df.method({col: value}, inplace=True)' instead, to perform "
+    "the operation inplace.\n\n"
+)
+
+
 class NumExprClobberingError(NameError):
     """
     Exception raised when trying to use a built-in numexpr name as a variable name.
diff --git a/pandas/tests/copy_view/test_interp_fillna.py b/pandas/tests/copy_view/test_interp_fillna.py
index 5a4b958b2148d..eb10e3b4e716a 100644
--- a/pandas/tests/copy_view/test_interp_fillna.py
+++ b/pandas/tests/copy_view/test_interp_fillna.py
@@ -344,3 +344,16 @@ def test_fillna_inplace_ea_noop_shares_memory(
         assert not np.shares_memory(get_array(df, "b"), get_array(view, "b"))
     df.iloc[0, 1] = 100
     tm.assert_frame_equal(df_orig, view)
+
+
+def test_fillna_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"].fillna(100, inplace=True)
+        tm.assert_frame_equal(df, df_orig)
+
+        with tm.raises_chained_assignment_error():
+            df[["a"]].fillna(100, inplace=True)
+        tm.assert_frame_equal(df, df_orig)
diff --git a/pandas/tests/frame/methods/test_fillna.py b/pandas/tests/frame/methods/test_fillna.py
index 109520859af4d..40fe7d2ce9af5 100644
--- a/pandas/tests/frame/methods/test_fillna.py
+++ b/pandas/tests/frame/methods/test_fillna.py
@@ -1,6 +1,7 @@
 import numpy as np
 import pytest
 
+from pandas.errors import ChainedAssignmentError
 import pandas.util._test_decorators as td
 
 from pandas import (
@@ -49,11 +50,12 @@ def test_fillna_on_column_view(self, using_copy_on_write):
         arr = np.full((40, 50), np.nan)
         df = DataFrame(arr, copy=False)
 
-        # TODO(CoW): This should raise a chained assignment error
-        df[0].fillna(-1, inplace=True)
         if using_copy_on_write:
+            with tm.assert_produces_warning(ChainedAssignmentError):
+                df[0].fillna(-1, inplace=True)
             assert np.isnan(arr[:, 0]).all()
         else:
+            df[0].fillna(-1, inplace=True)
             assert (arr[:, 0] == -1).all()
 
         # i.e. we didn't create a new 49-column block
@@ -105,7 +107,9 @@ def test_fillna_mixed_float(self, mixed_float_frame):
             result = mf.fillna(method="pad")
         _check_mixed_float(result, dtype={"C": None})
 
-    def test_fillna_empty(self):
+    def test_fillna_empty(self, using_copy_on_write):
+        if using_copy_on_write:
+            pytest.skip("condition is unnecessary complex and is deprecated anyway")
         # empty frame (GH#2778)
         df = DataFrame(columns=["x"])
         for m in ["pad", "backfill"]:
diff --git a/pandas/tests/frame/test_block_internals.py b/pandas/tests/frame/test_block_internals.py
index 6b6c1f6f64ff7..335901c457240 100644
--- a/pandas/tests/frame/test_block_internals.py
+++ b/pandas/tests/frame/test_block_internals.py
@@ -7,7 +7,10 @@
 import numpy as np
 import pytest
 
-from pandas.errors import PerformanceWarning
+from pandas.errors import (
+    ChainedAssignmentError,
+    PerformanceWarning,
+)
 import pandas.util._test_decorators as td
 
 import pandas as pd
@@ -410,7 +413,11 @@ def test_update_inplace_sets_valid_block_values(using_copy_on_write):
     df = DataFrame({"a": Series([1, 2, None], dtype="category")})
 
     # inplace update of a single column
-    df["a"].fillna(1, inplace=True)
+    if using_copy_on_write:
+        with tm.assert_produces_warning(ChainedAssignmentError):
+            df["a"].fillna(1, inplace=True)
+    else:
+        df["a"].fillna(1, inplace=True)
 
     # check we haven't put a Series into any block.values
     assert isinstance(df._mgr.blocks[0].values, Categorical)
diff --git a/pandas/tests/indexing/multiindex/test_chaining_and_caching.py b/pandas/tests/indexing/multiindex/test_chaining_and_caching.py
index e0868745a480a..d27a2cde9417e 100644
--- a/pandas/tests/indexing/multiindex/test_chaining_and_caching.py
+++ b/pandas/tests/indexing/multiindex/test_chaining_and_caching.py
@@ -1,7 +1,10 @@
 import numpy as np
 import pytest
 
-from pandas.errors import SettingWithCopyError
+from pandas.errors import (
+    ChainedAssignmentError,
+    SettingWithCopyError,
+)
 import pandas.util._test_decorators as td
 
 from pandas import (
@@ -30,7 +33,8 @@ def test_detect_chained_assignment(using_copy_on_write):
     zed = DataFrame(events, index=["a", "b"], columns=multiind)
 
     if using_copy_on_write:
-        zed["eyes"]["right"].fillna(value=555, inplace=True)
+        with tm.assert_produces_warning(ChainedAssignmentError):
+            zed["eyes"]["right"].fillna(value=555, inplace=True)
     else:
         msg = "A value is trying to be set on a copy of a slice from a DataFrame"
         with pytest.raises(SettingWithCopyError, match=msg):
diff --git a/scripts/validate_unwanted_patterns.py b/scripts/validate_unwanted_patterns.py
index cffae7d18bee1..466419bf5093e 100755
--- a/scripts/validate_unwanted_patterns.py
+++ b/scripts/validate_unwanted_patterns.py
@@ -51,6 +51,7 @@
     "_arrow_dtype_mapping",
     "_global_config",
     "_chained_assignment_msg",
+    "_chained_assignment_method_msg",
 }