diff --git a/doc/source/whatsnew/v2.2.1.rst b/doc/source/whatsnew/v2.2.1.rst
index eb6e50c1be160..434a8fd3ea6b4 100644
--- a/doc/source/whatsnew/v2.2.1.rst
+++ b/doc/source/whatsnew/v2.2.1.rst
@@ -24,6 +24,7 @@ Fixed regressions
 - Fixed regression in :meth:`DataFrame.groupby` raising ``ValueError`` when grouping by a :class:`Series` in some cases (:issue:`57276`)
 - Fixed regression in :meth:`DataFrame.loc` raising ``IndexError`` for non-unique, masked dtype indexes where result has more than 10,000 rows (:issue:`57027`)
 - Fixed regression in :meth:`DataFrame.merge` raising ``ValueError`` for certain types of 3rd-party extension arrays (:issue:`57316`)
+- Fixed regression in :meth:`DataFrame.shift` raising ``AssertionError`` for ``axis=1`` and empty :class:`DataFrame` (:issue:`57301`)
 - Fixed regression in :meth:`DataFrame.sort_index` not producing a stable sort for a index with duplicates (:issue:`57151`)
 - Fixed regression in :meth:`DataFrame.to_dict` with ``orient='list'`` and datetime or timedelta types returning integers (:issue:`54824`)
 - Fixed regression in :meth:`DataFrame.to_json` converting nullable integers to floats (:issue:`57224`)
diff --git a/pandas/core/frame.py b/pandas/core/frame.py
index 734756cb8f7c8..b531ddc418df1 100644
--- a/pandas/core/frame.py
+++ b/pandas/core/frame.py
@@ -5859,6 +5859,9 @@ def shift(
             )
             fill_value = lib.no_default
 
+        if self.empty:
+            return self.copy()
+
         axis = self._get_axis_number(axis)
 
         if is_list_like(periods):
diff --git a/pandas/tests/frame/methods/test_shift.py b/pandas/tests/frame/methods/test_shift.py
index b21aa2d687682..abb30595fdcb8 100644
--- a/pandas/tests/frame/methods/test_shift.py
+++ b/pandas/tests/frame/methods/test_shift.py
@@ -756,3 +756,9 @@ def test_shift_with_iterable_check_other_arguments(self):
         msg = "Cannot specify `suffix` if `periods` is an int."
         with pytest.raises(ValueError, match=msg):
             df.shift(1, suffix="fails")
+
+    def test_shift_axis_one_empty(self):
+        # GH#57301
+        df = DataFrame()
+        result = df.shift(1, axis=1)
+        tm.assert_frame_equal(result, df)