diff --git a/doc/source/whatsnew/v1.4.2.rst b/doc/source/whatsnew/v1.4.2.rst
index 3523f691cae8f..4cbb8118055af 100644
--- a/doc/source/whatsnew/v1.4.2.rst
+++ b/doc/source/whatsnew/v1.4.2.rst
@@ -19,6 +19,7 @@ Fixed regressions
 - Fixed memory performance regression in :meth:`Series.fillna` when called on a :class:`DataFrame` column with ``inplace=True`` (:issue:`46149`)
 - Provided an alternative solution for passing custom Excel formats in :meth:`.Styler.to_excel`, which was a regression based on stricter CSS validation. Examples available in the documentation for :meth:`.Styler.format` (:issue:`46152`)
 - Fixed regression in :meth:`DataFrame.replace` when a replacement value was also a target for replacement (:issue:`46306`)
+- Fixed regression in :meth:`DataFrame.replace` when the replacement value was explicitly ``None`` when passed in a dictionary to ``to_replace`` (:issue:`45601`, :issue:`45836`)
 - Fixed regression when setting values with :meth:`DataFrame.loc` losing :class:`MultiIndex` names if :class:`DataFrame`  was empty before (:issue:`46317`)
 -
 
diff --git a/pandas/core/internals/blocks.py b/pandas/core/internals/blocks.py
index cdf2c47ad3f60..2ff195fa8e5d2 100644
--- a/pandas/core/internals/blocks.py
+++ b/pandas/core/internals/blocks.py
@@ -777,6 +777,13 @@ def _replace_coerce(
                 mask=mask,
             )
         else:
+            if value is None:
+                # gh-45601, gh-45836
+                nb = self.astype(np.dtype(object), copy=False)
+                if nb is self and not inplace:
+                    nb = nb.copy()
+                putmask_inplace(nb.values, mask, value)
+                return [nb]
             return self.replace(
                 to_replace=to_replace, value=value, inplace=inplace, mask=mask
             )
diff --git a/pandas/tests/frame/methods/test_replace.py b/pandas/tests/frame/methods/test_replace.py
index d8cd477cdcff8..870a64cfa59c9 100644
--- a/pandas/tests/frame/methods/test_replace.py
+++ b/pandas/tests/frame/methods/test_replace.py
@@ -661,6 +661,20 @@ def test_replace_simple_nested_dict_with_nonexistent_value(self):
         result = df.replace({"col": {-1: "-", 1: "a", 4: "b"}})
         tm.assert_frame_equal(expected, result)
 
+    def test_replace_NA_with_None(self):
+        # gh-45601
+        df = DataFrame({"value": [42, None]}).astype({"value": "Int64"})
+        result = df.replace({pd.NA: None})
+        expected = DataFrame({"value": [42, None]}, dtype=object)
+        tm.assert_frame_equal(result, expected)
+
+    def test_replace_NAT_with_None(self):
+        # gh-45836
+        df = DataFrame([pd.NaT, pd.NaT])
+        result = df.replace({pd.NaT: None, np.NaN: None})
+        expected = DataFrame([None, None])
+        tm.assert_frame_equal(result, expected)
+
     def test_replace_value_is_none(self, datetime_frame):
         orig_value = datetime_frame.iloc[0, 0]
         orig2 = datetime_frame.iloc[1, 0]