diff --git a/doc/source/whatsnew/v1.4.4.rst b/doc/source/whatsnew/v1.4.4.rst
index dce8fb60ecdd6..b4224b5b210e0 100644
--- a/doc/source/whatsnew/v1.4.4.rst
+++ b/doc/source/whatsnew/v1.4.4.rst
@@ -16,6 +16,7 @@ Fixed regressions
 ~~~~~~~~~~~~~~~~~
 - Fixed regression in :func:`concat` materializing :class:`Index` during sorting even if :class:`Index` was already sorted (:issue:`47501`)
 - Fixed regression in :meth:`DataFrame.loc` not updating the cache correctly after values were set (:issue:`47867`)
+- Fixed regression in :meth:`DataFrame.loc` not aligning index in some cases when setting a :class:`DataFrame` (:issue:`47578`)
 - Fixed regression in setting ``None`` or non-string value into a ``string``-dtype Series using a mask (:issue:`47628`)
 -
 
diff --git a/pandas/core/frame.py b/pandas/core/frame.py
index 5b25f5be01d29..fcd822988de20 100644
--- a/pandas/core/frame.py
+++ b/pandas/core/frame.py
@@ -4527,8 +4527,8 @@ def _sanitize_column(self, value) -> ArrayLike:
         """
         self._ensure_valid_index(value)
 
-        # We should never get here with DataFrame value
-        if isinstance(value, Series):
+        # We can get there through loc single_block_path
+        if isinstance(value, (DataFrame, Series)):
             return _reindex_for_setitem(value, self.index)
 
         if is_list_like(value):
diff --git a/pandas/tests/frame/indexing/test_indexing.py b/pandas/tests/frame/indexing/test_indexing.py
index a7af569e397eb..4dc9cbdb7b34d 100644
--- a/pandas/tests/frame/indexing/test_indexing.py
+++ b/pandas/tests/frame/indexing/test_indexing.py
@@ -1323,6 +1323,15 @@ def test_loc_internals_not_updated_correctly(self):
         )
         tm.assert_series_equal(result, expected)
 
+    @pytest.mark.parametrize("val", ["x", 1])
+    @pytest.mark.parametrize("idxr", ["a", ["a"]])
+    def test_loc_setitem_rhs_frame(self, idxr, val):
+        # GH#47578
+        df = DataFrame({"a": [1, 2]})
+        df.loc[:, "a"] = DataFrame({"a": [val, 11]}, index=[1, 2])
+        expected = DataFrame({"a": [np.nan, val]})
+        tm.assert_frame_equal(df, expected)
+
 
 class TestDataFrameIndexingUInt64:
     def test_setitem(self, uint64_frame):
diff --git a/pandas/tests/frame/indexing/test_setitem.py b/pandas/tests/frame/indexing/test_setitem.py
index 673d347917832..c438dc78ce397 100644
--- a/pandas/tests/frame/indexing/test_setitem.py
+++ b/pandas/tests/frame/indexing/test_setitem.py
@@ -699,6 +699,13 @@ def test_setitem_npmatrix_2d(self):
 
         tm.assert_frame_equal(df, expected)
 
+    def test_setitem_rhs_dataframe(self):
+        # GH#47578
+        df = DataFrame({"a": [1, 2]})
+        df["a"] = DataFrame({"a": [10, 11]}, index=[1, 2])
+        expected = DataFrame({"a": [np.nan, 10]})
+        tm.assert_frame_equal(df, expected)
+
 
 class TestSetitemTZAwareValues:
     @pytest.fixture