diff --git a/doc/source/whatsnew/v1.3.3.rst b/doc/source/whatsnew/v1.3.3.rst
index df09873742edd..126e0819febb9 100644
--- a/doc/source/whatsnew/v1.3.3.rst
+++ b/doc/source/whatsnew/v1.3.3.rst
@@ -24,6 +24,7 @@ Fixed regressions
 - Fixed regression in :meth:`read_parquet` where the ``fastparquet`` engine would not work properly with fastparquet 0.7.0 (:issue:`43075`)
 - Fixed regression in :meth:`DataFrame.loc.__setitem__` raising ``ValueError`` when setting array as cell value (:issue:`43422`)
 - Fixed regression in :func:`is_list_like` where objects with ``__iter__`` set to ``None`` would be identified as iterable (:issue:`43373`)
+- Fixed regression in :meth:`DataFrame.__getitem__` raising error for slice of :class:`DatetimeIndex` when index is non monotonic (:issue:`43223`)
 - Fixed regression in :meth:`.Resampler.aggregate` when used after column selection would raise if ``func`` is a list of aggregation functions (:issue:`42905`)
 - Fixed regression in :meth:`DataFrame.corr` where Kendall correlation would produce incorrect results for columns with repeated values (:issue:`43401`)
 - Fixed regression in :meth:`Series.fillna` raising ``TypeError`` when filling ``float`` ``Series`` with list-like fill value having a dtype which couldn't cast lostlessly (like ``float32`` filled with ``float64``) (:issue:`43424`)
diff --git a/pandas/core/frame.py b/pandas/core/frame.py
index 304de0a00cded..7686743dd1b6d 100644
--- a/pandas/core/frame.py
+++ b/pandas/core/frame.py
@@ -3473,6 +3473,9 @@ def __getitem__(self, key):
                 indexer = lib.maybe_indices_to_slice(
                     indexer.astype(np.intp, copy=False), len(self)
                 )
+                if isinstance(indexer, np.ndarray):
+                    # GH#43223 If we can not convert, use take
+                    return self.take(indexer, axis=0)
             # either we have a slice or we have a string that can be converted
             #  to a slice for partial-string date indexing
             return self._slice(indexer, axis=0)
diff --git a/pandas/tests/frame/indexing/test_getitem.py b/pandas/tests/frame/indexing/test_getitem.py
index 1b350b11b47e9..3028a433f2dae 100644
--- a/pandas/tests/frame/indexing/test_getitem.py
+++ b/pandas/tests/frame/indexing/test_getitem.py
@@ -8,6 +8,7 @@
     CategoricalDtype,
     CategoricalIndex,
     DataFrame,
+    DatetimeIndex,
     Index,
     MultiIndex,
     Series,
@@ -364,3 +365,26 @@ def test_getitem_slice_float64(self, frame_or_series):
 
         result = obj.loc[start:end]
         tm.assert_equal(result, expected)
+
+    def test_getitem_datetime_slice(self):
+        # GH#43223
+        df = DataFrame(
+            {"a": 0},
+            index=DatetimeIndex(
+                [
+                    "11.01.2011 22:00",
+                    "11.01.2011 23:00",
+                    "12.01.2011 00:00",
+                    "2011-01-13 00:00",
+                ]
+            ),
+        )
+        with tm.assert_produces_warning(FutureWarning):
+            result = df["2011-01-01":"2011-11-01"]
+        expected = DataFrame(
+            {"a": 0},
+            index=DatetimeIndex(
+                ["11.01.2011 22:00", "11.01.2011 23:00", "2011-01-13 00:00"]
+            ),
+        )
+        tm.assert_frame_equal(result, expected)