diff --git a/doc/source/whatsnew/v3.0.0.rst b/doc/source/whatsnew/v3.0.0.rst
index 94c289ef3ace7..5cc258a54fa48 100644
--- a/doc/source/whatsnew/v3.0.0.rst
+++ b/doc/source/whatsnew/v3.0.0.rst
@@ -798,6 +798,7 @@ Other
 - Bug in :meth:`Series.dt` methods in :class:`ArrowDtype` that were returning incorrect values. (:issue:`57355`)
 - Bug in :meth:`Series.rank` that doesn't preserve missing values for nullable integers when ``na_option='keep'``. (:issue:`56976`)
 - Bug in :meth:`Series.replace` and :meth:`DataFrame.replace` inconsistently replacing matching instances when ``regex=True`` and missing values are present. (:issue:`56599`)
+- Bug in :meth:`Series.replace` and :meth:`DataFrame.replace` throwing ``ValueError`` when ``regex=True`` and all NA values. (:issue:`60688`)
 - Bug in :meth:`Series.to_string` when series contains complex floats with exponents (:issue:`60405`)
 - Bug in :meth:`read_csv` where chained fsspec TAR file and ``compression="infer"`` fails with ``tarfile.ReadError`` (:issue:`60028`)
 - Bug in Dataframe Interchange Protocol implementation was returning incorrect results for data buffers' associated dtype, for string and datetime columns (:issue:`54781`)
diff --git a/pandas/core/array_algos/replace.py b/pandas/core/array_algos/replace.py
index a9ad66b7cb2e5..debd6368e98a4 100644
--- a/pandas/core/array_algos/replace.py
+++ b/pandas/core/array_algos/replace.py
@@ -89,7 +89,8 @@ def _check_comparison_types(
         op = np.vectorize(
             lambda x: bool(re.search(b, x))
             if isinstance(x, str) and isinstance(b, (str, Pattern))
-            else False
+            else False,
+            otypes=[bool],
         )
 
     # GH#32621 use mask to avoid comparing to NAs
diff --git a/pandas/tests/frame/methods/test_replace.py b/pandas/tests/frame/methods/test_replace.py
index b2320798ea9a2..c95806d9316bf 100644
--- a/pandas/tests/frame/methods/test_replace.py
+++ b/pandas/tests/frame/methods/test_replace.py
@@ -713,6 +713,13 @@ def test_replace_with_None_keeps_categorical(self):
         )
         tm.assert_frame_equal(result, expected)
 
+    def test_replace_all_NA(self):
+        # GH#60688
+        df = DataFrame({"ticker": ["#1234#"], "name": [None]})
+        result = df.replace({col: {r"^#": "$"} for col in df.columns}, regex=True)
+        expected = DataFrame({"ticker": ["$1234#"], "name": [None]})
+        tm.assert_frame_equal(result, expected)
+
     def test_replace_value_is_none(self, datetime_frame):
         orig_value = datetime_frame.iloc[0, 0]
         orig2 = datetime_frame.iloc[1, 0]
diff --git a/pandas/tests/series/methods/test_replace.py b/pandas/tests/series/methods/test_replace.py
index ecfe3d1b39d31..abd5d075ea3d5 100644
--- a/pandas/tests/series/methods/test_replace.py
+++ b/pandas/tests/series/methods/test_replace.py
@@ -708,3 +708,10 @@ def test_replace_ea_float_with_bool(self):
         expected = ser.copy()
         result = ser.replace(0.0, True)
         tm.assert_series_equal(result, expected)
+
+    def test_replace_all_NA(self):
+        # GH#60688
+        df = pd.Series([pd.NA, pd.NA])
+        result = df.replace({r"^#": "$"}, regex=True)
+        expected = pd.Series([pd.NA, pd.NA])
+        tm.assert_series_equal(result, expected)