diff --git a/doc/source/whatsnew/v3.0.0.rst b/doc/source/whatsnew/v3.0.0.rst
index edd205860b4e4..0bd68a539a2ba 100644
--- a/doc/source/whatsnew/v3.0.0.rst
+++ b/doc/source/whatsnew/v3.0.0.rst
@@ -690,6 +690,7 @@ Indexing
 ^^^^^^^^
 - Bug in :meth:`DataFrame.__getitem__` returning modified columns when called with ``slice`` in Python 3.12 (:issue:`57500`)
 - Bug in :meth:`DataFrame.from_records` throwing a ``ValueError`` when passed an empty list in ``index`` (:issue:`58594`)
+- Bug in :meth:`DataFrame.loc` with inconsistent behavior of loc-set with 2 given indexes to Series (:issue:`59933`)
 - Bug in :meth:`MultiIndex.insert` when a new value inserted to a datetime-like level gets cast to ``NaT`` and fails indexing (:issue:`60388`)
 - Bug in printing :attr:`Index.names` and :attr:`MultiIndex.levels` would not escape single quotes (:issue:`60190`)
 
diff --git a/pandas/core/indexing.py b/pandas/core/indexing.py
index 8a493fef54d3b..bcb27d0320c91 100644
--- a/pandas/core/indexing.py
+++ b/pandas/core/indexing.py
@@ -2349,11 +2349,17 @@ def _align_series(
 
         if isinstance(indexer, tuple):
             # flatten np.ndarray indexers
+            if (
+                len(indexer) == 2
+                and isinstance(indexer[1], np.ndarray)
+                and indexer[1].dtype == np.bool_
+            ):
+                indexer = (indexer[0], np.where(indexer[1])[0])
+
             def ravel(i):
                 return i.ravel() if isinstance(i, np.ndarray) else i
 
             indexer = tuple(map(ravel, indexer))
-
             aligners = [not com.is_null_slice(idx) for idx in indexer]
             sum_aligners = sum(aligners)
             single_aligner = sum_aligners == 1
@@ -2371,12 +2377,15 @@ def ravel(i):
 
             # we have a frame, with multiple indexers on both axes; and a
             # series, so need to broadcast (see GH5206)
-            if sum_aligners == self.ndim and all(is_sequence(_) for _ in indexer):
+            if all(is_sequence(_) or isinstance(_, slice) for _ in indexer):
                 ser_values = ser.reindex(obj.axes[0][indexer[0]])._values
 
                 # single indexer
                 if len(indexer) > 1 and not multiindex_indexer:
-                    len_indexer = len(indexer[1])
+                    if isinstance(indexer[1], slice):
+                        len_indexer = len(obj.axes[1][indexer[1]])
+                    else:
+                        len_indexer = len(indexer[1])
                     ser_values = (
                         np.tile(ser_values, len_indexer).reshape(len_indexer, -1).T
                     )
diff --git a/pandas/tests/indexing/test_loc.py b/pandas/tests/indexing/test_loc.py
index 17e610bda93e4..8838fc7eed2f7 100644
--- a/pandas/tests/indexing/test_loc.py
+++ b/pandas/tests/indexing/test_loc.py
@@ -3296,6 +3296,66 @@ def test_loc_reindexing_of_empty_index(self):
         expected = DataFrame(index=[1, 1, 2, 2], data=["1", "1", "2", "2"])
         tm.assert_frame_equal(df, expected)
 
+    @pytest.mark.parametrize(
+        "df, row_index, col_index, expected_df",
+        [
+            [
+                DataFrame([[1, 2, 3], [4, 5, 6]], columns=list("ABC")),
+                slice(0, 3),
+                ["A", "B", "C"],
+                DataFrame([[10, 10, 10], [20, 20, 20]], columns=list("ABC")),
+            ],
+            [
+                DataFrame([[1, 2, 3], [4, 5, 6]], columns=list("ABC")),
+                slice(None),
+                ["A", "B", "C"],
+                DataFrame([[10, 10, 10], [20, 20, 20]], columns=list("ABC")),
+            ],
+            [
+                DataFrame([[1, 2, 3], [4, 5, 6], [7, 8, 9]], columns=list("ABC")),
+                [True, True, True],
+                ["A", "B", "C"],
+                DataFrame(
+                    [[10, 10, 10], [20, 20, 20], [30, 30, 30]], columns=list("ABC")
+                ),
+            ],
+            [
+                DataFrame([[1, 2, 3], [4, 5, 6], [7, 8, 9]], columns=list("ABC")),
+                slice(0, 4),
+                ["A", "B", "C"],
+                DataFrame(
+                    [[10, 10, 10], [20, 20, 20], [30, 30, 30]], columns=list("ABC")
+                ),
+            ],
+            [
+                DataFrame([[1, 2, 3], [4, 5, 6], [7, 8, 9]], columns=list("ABC")),
+                slice(None),
+                slice("A", "C"),
+                DataFrame(
+                    [[10, 10, 10], [20, 20, 20], [30, 30, 30]], columns=list("ABC")
+                ),
+            ],
+            [
+                DataFrame([[1, 2, 3], [4, 5, 6], [7, 8, 9]], columns=list("ABC")),
+                slice(None),
+                Series(
+                    {
+                        "A": True,
+                        "C": False,
+                        "B": True,
+                    }
+                ),
+                DataFrame([[10, 10, 3], [20, 20, 6], [30, 30, 9]], columns=list("ABC")),
+            ],
+        ],
+    )
+    def test_loc_set_series_to_multiple_columns(
+        self, df, row_index, col_index, expected_df
+    ):
+        # GH 59933
+        df.loc[row_index, col_index] = Series([10, 20, 30])
+        tm.assert_frame_equal(df, expected_df)
+
     def test_loc_setitem_matching_index(self):
         # GH 25548
         s = Series(0.0, index=list("abcd"))