diff --git a/pandas/core/indexing.py b/pandas/core/indexing.py
index 5f9bc142c5836..4a251ae0d93da 100644
--- a/pandas/core/indexing.py
+++ b/pandas/core/indexing.py
@@ -53,6 +53,7 @@
     is_empty_indexer,
     is_exact_shape_match,
     is_list_like_indexer,
+    is_scalar_indexer,
     length_of_indexer,
 )
 from pandas.core.indexes.api import (
@@ -669,6 +670,71 @@ def _get_setitem_indexer(self, key):
 
         return self._convert_to_indexer(key, axis=0)
 
+    @final
+    def _maybe_mask_setitem_value(self, indexer, value):
+        """
+        If we have obj.iloc[mask] = series_or_frame and series_or_frame has the
+        same length as obj, we treat this as obj.iloc[mask] = series_or_frame[mask],
+        similar to Series.__setitem__.
+
+        Note this is only for loc, not iloc.
+        """
+
+        if (
+            isinstance(indexer, tuple)
+            and len(indexer) == 2
+            and isinstance(value, (ABCSeries, ABCDataFrame))
+        ):
+            pi, icols = indexer
+            ndim = value.ndim
+            if com.is_bool_indexer(pi) and len(value) == len(pi):
+                newkey = pi.nonzero()[0]
+
+                if is_scalar_indexer(icols, self.ndim - 1) and ndim == 1:
+                    # e.g. test_loc_setitem_boolean_mask_allfalse
+                    if len(newkey) == 0:
+                        # FIXME: kludge for test_loc_setitem_boolean_mask_allfalse
+                        # TODO(GH#45333): may be fixed when deprecation is enforced
+
+                        value = value.iloc[:0]
+                    else:
+                        # test_loc_setitem_ndframe_values_alignment
+                        value = self.obj.iloc._align_series(indexer, value)
+                    indexer = (newkey, icols)
+
+                elif (
+                    isinstance(icols, np.ndarray)
+                    and icols.dtype.kind == "i"
+                    and len(icols) == 1
+                ):
+                    if ndim == 1:
+                        # We implicitly broadcast, though numpy does not, see
+                        # github.com/pandas-dev/pandas/pull/45501#discussion_r789071825
+                        if len(newkey) == 0:
+                            # FIXME: kludge for
+                            #  test_setitem_loc_only_false_indexer_dtype_changed
+                            #  TODO(GH#45333): may be fixed when deprecation is enforced
+                            value = value.iloc[:0]
+                        else:
+                            # test_loc_setitem_ndframe_values_alignment
+                            value = self.obj.iloc._align_series(indexer, value)
+                        indexer = (newkey, icols)
+
+                    elif ndim == 2 and value.shape[1] == 1:
+                        if len(newkey) == 0:
+                            # FIXME: kludge for
+                            #  test_loc_setitem_all_false_boolean_two_blocks
+                            #  TODO(GH#45333): may be fixed when deprecation is enforced
+                            value = value.iloc[:0]
+                        else:
+                            # test_loc_setitem_ndframe_values_alignment
+                            value = self.obj.iloc._align_frame(indexer, value)
+                        indexer = (newkey, icols)
+        elif com.is_bool_indexer(indexer):
+            indexer = indexer.nonzero()[0]
+
+        return indexer, value
+
     @final
     def _tupleize_axis_indexer(self, key) -> tuple:
         """
@@ -1299,8 +1365,7 @@ def _convert_to_indexer(self, key, axis: int):
 
             if com.is_bool_indexer(key):
                 key = check_bool_indexer(labels, key)
-                (inds,) = key.nonzero()
-                return inds
+                return key
             else:
                 return self._get_listlike_indexer(key, axis)[1]
         else:
@@ -1696,6 +1761,10 @@ def _setitem_with_indexer(self, indexer, value, name="iloc"):
                 self._setitem_with_indexer_missing(indexer, value)
                 return
 
+        if name == "loc":
+            # must come after setting of missing
+            indexer, value = self._maybe_mask_setitem_value(indexer, value)
+
         # align and set the values
         if take_split_path:
             # We have to operate column-wise
diff --git a/pandas/core/internals/blocks.py b/pandas/core/internals/blocks.py
index 3d4f53530b89c..0cdd6425c2657 100644
--- a/pandas/core/internals/blocks.py
+++ b/pandas/core/internals/blocks.py
@@ -932,7 +932,7 @@ def setitem(self, indexer, value):
 
         if is_empty_indexer(indexer):
             # GH#8669 empty indexers, test_loc_setitem_boolean_mask_allfalse
-            pass
+            values[indexer] = value
 
         elif is_scalar_indexer(indexer, self.ndim):
             # setting a single element for each dim and with a rhs that could
diff --git a/pandas/tests/indexing/test_loc.py b/pandas/tests/indexing/test_loc.py
index 4b751fa7d5e3e..73beb04fca81f 100644
--- a/pandas/tests/indexing/test_loc.py
+++ b/pandas/tests/indexing/test_loc.py
@@ -2446,6 +2446,31 @@ def test_loc_setitem_boolean_and_column(self, float_frame):
 
         tm.assert_frame_equal(float_frame, expected)
 
+    def test_loc_setitem_ndframe_values_alignment(self):
+        # GH#45501
+        df = DataFrame({"a": [1, 2, 3], "b": [4, 5, 6]})
+        df.loc[[False, False, True], ["a"]] = DataFrame(
+            {"a": [10, 20, 30]}, index=[2, 1, 0]
+        )
+
+        expected = DataFrame({"a": [1, 2, 10], "b": [4, 5, 6]})
+        tm.assert_frame_equal(df, expected)
+
+        # same thing with Series RHS
+        df = DataFrame({"a": [1, 2, 3], "b": [4, 5, 6]})
+        df.loc[[False, False, True], ["a"]] = Series([10, 11, 12], index=[2, 1, 0])
+        tm.assert_frame_equal(df, expected)
+
+        # same thing but setting "a" instead of ["a"]
+        df = DataFrame({"a": [1, 2, 3], "b": [4, 5, 6]})
+        df.loc[[False, False, True], "a"] = Series([10, 11, 12], index=[2, 1, 0])
+        tm.assert_frame_equal(df, expected)
+
+        df = DataFrame({"a": [1, 2, 3], "b": [4, 5, 6]})
+        ser = df["a"]
+        ser.loc[[False, False, True]] = Series([10, 11, 12], index=[2, 1, 0])
+        tm.assert_frame_equal(df, expected)
+
 
 class TestLocListlike:
     @pytest.mark.parametrize("box", [lambda x: x, np.asarray, list])