diff --git a/doc/source/whatsnew/v1.3.5.rst b/doc/source/whatsnew/v1.3.5.rst
index 5e05bda331bb2..c53707610db37 100644
--- a/doc/source/whatsnew/v1.3.5.rst
+++ b/doc/source/whatsnew/v1.3.5.rst
@@ -22,6 +22,8 @@ Fixed regressions
 - Fixed regression in :meth:`Series.duplicated` and :meth:`Series.drop_duplicates` when Series has :class:`Categorical` dtype with boolean categories (:issue:`44351`)
 - Fixed regression in :meth:`.GroupBy.sum` with ``timedelta64[ns]`` dtype containing ``NaT`` failing to treat that value as NA (:issue:`42659`)
 - Fixed regression in :meth:`.RollingGroupby.cov` and :meth:`.RollingGroupby.corr` when ``other`` had the same shape as each group would incorrectly return superfluous groups in the result (:issue:`42915`)
+- Fixed regression where a single column ``np.matrix`` was no longer coerced to a 1d ``np.ndarray`` when added to a :class:`DataFrame` (:issue:`42376`)
+
 
 .. ---------------------------------------------------------------------------
 
diff --git a/pandas/core/construction.py b/pandas/core/construction.py
index 8261162afe187..cf8cd070ec562 100644
--- a/pandas/core/construction.py
+++ b/pandas/core/construction.py
@@ -528,6 +528,8 @@ def sanitize_array(
 
     # GH#846
     if isinstance(data, np.ndarray):
+        if isinstance(data, np.matrix):
+            data = data.A
 
         if dtype is not None and is_float_dtype(data.dtype) and is_integer_dtype(dtype):
             # possibility of nan -> garbage
diff --git a/pandas/tests/frame/indexing/test_setitem.py b/pandas/tests/frame/indexing/test_setitem.py
index 9868cec633dff..cd0a0a0467742 100644
--- a/pandas/tests/frame/indexing/test_setitem.py
+++ b/pandas/tests/frame/indexing/test_setitem.py
@@ -680,6 +680,25 @@ def test_boolean_mask_nullable_int64(self):
         )
         tm.assert_frame_equal(result, expected)
 
+    # TODO(ArrayManager) set column with 2d column array, see #44788
+    @td.skip_array_manager_not_yet_implemented
+    def test_setitem_npmatrix_2d(self):
+        # GH#42376
+        # for use-case df["x"] = sparse.random(10, 10).mean(axis=1)
+        expected = DataFrame(
+            {"np-array": np.ones(10), "np-matrix": np.ones(10)}, index=np.arange(10)
+        )
+
+        a = np.ones((10, 1))
+        df = DataFrame(index=np.arange(10))
+        df["np-array"] = a
+
+        # Instantiation of `np.matrix` gives PendingDeprecationWarning
+        with tm.assert_produces_warning(PendingDeprecationWarning):
+            df["np-matrix"] = np.matrix(a)
+
+        tm.assert_frame_equal(df, expected)
+
 
 class TestSetitemTZAwareValues:
     @pytest.fixture