diff --git a/doc/source/whatsnew/v1.4.0.rst b/doc/source/whatsnew/v1.4.0.rst
index 71903d10a6983..648cef5b46103 100644
--- a/doc/source/whatsnew/v1.4.0.rst
+++ b/doc/source/whatsnew/v1.4.0.rst
@@ -822,7 +822,7 @@ Other
 - Bug in :meth:`FloatingArray.equals` failing to consider two arrays equal if they contain ``np.nan`` values (:issue:`44382`)
 - Bug in :meth:`DataFrame.shift` with ``axis=1`` and ``ExtensionDtype`` columns incorrectly raising when an incompatible ``fill_value`` is passed (:issue:`44564`)
 - Bug in :meth:`DataFrame.diff` when passing a NumPy integer object instead of an ``int`` object (:issue:`44572`)
--
+- Bug in :meth:`Series.replace` raising ``ValueError`` when using ``regex=True`` with a :class:`Series` containing ``np.nan`` values (:issue:`43344`)
 
 .. ***DO NOT USE THIS SECTION***
 
diff --git a/pandas/core/array_algos/replace.py b/pandas/core/array_algos/replace.py
index df4407067b131..4d1fb8f33e5ad 100644
--- a/pandas/core/array_algos/replace.py
+++ b/pandas/core/array_algos/replace.py
@@ -108,7 +108,7 @@ def _check_comparison_types(
         # The shape of the mask can differ to that of the result
         # since we may compare only a subset of a's or b's elements
         tmp = np.zeros(mask.shape, dtype=np.bool_)
-        tmp[mask] = result
+        np.place(tmp, mask, result)
         result = tmp
 
     _check_comparison_types(result, a, b)
diff --git a/pandas/tests/series/methods/test_replace.py b/pandas/tests/series/methods/test_replace.py
index 8283604b99d32..28a0df99bb2b6 100644
--- a/pandas/tests/series/methods/test_replace.py
+++ b/pandas/tests/series/methods/test_replace.py
@@ -499,3 +499,16 @@ def test_replace_with_compiled_regex(self):
         result = s.replace({regex: "z"}, regex=True)
         expected = pd.Series(["z", "b", "c"])
         tm.assert_series_equal(result, expected)
+
+    def test_pandas_replace_na(self):
+        # GH#43344
+        ser = pd.Series(["AA", "BB", "CC", "DD", "EE", "", pd.NA], dtype="string")
+        regex_mapping = {
+            "AA": "CC",
+            "BB": "CC",
+            "EE": "CC",
+            "CC": "CC-REPL",
+        }
+        result = ser.replace(regex_mapping, regex=True)
+        exp = pd.Series(["CC", "CC", "CC-REPL", "DD", "CC", "", pd.NA], dtype="string")
+        tm.assert_series_equal(result, exp)