diff --git a/doc/source/whatsnew/v1.3.0.rst b/doc/source/whatsnew/v1.3.0.rst
index 24725484bd3c6..a530fe4028ce4 100644
--- a/doc/source/whatsnew/v1.3.0.rst
+++ b/doc/source/whatsnew/v1.3.0.rst
@@ -53,6 +53,7 @@ Other enhancements
 - :meth:`DataFrame.apply` can now accept non-callable DataFrame properties as strings, e.g. ``df.apply("size")``, which was already the case for :meth:`Series.apply` (:issue:`39116`)
 - :meth:`Series.apply` can now accept list-like or dictionary-like arguments that aren't lists or dictionaries, e.g. ``ser.apply(np.array(["sum", "mean"]))``, which was already the case for :meth:`DataFrame.apply` (:issue:`39140`)
 - :meth:`.Styler.set_tooltips` allows on hover tooltips to be added to styled HTML dataframes.
+- :meth:`Series.loc.__getitem__` and :meth:`Series.loc.__setitem__` with :class:`MultiIndex` now raising helpful error message when indexer has too many dimensions (:issue:`35349`)
 
 .. ---------------------------------------------------------------------------
 
diff --git a/pandas/core/indexing.py b/pandas/core/indexing.py
index 998a34ce834ea..9185098ad48bf 100644
--- a/pandas/core/indexing.py
+++ b/pandas/core/indexing.py
@@ -846,6 +846,11 @@ def _getitem_nested_tuple(self, tup: Tuple):
             if self.name != "loc":
                 # This should never be reached, but lets be explicit about it
                 raise ValueError("Too many indices")
+            if isinstance(self.obj, ABCSeries) and any(
+                isinstance(k, tuple) for k in tup
+            ):
+                # GH#35349 Raise if tuple in tuple for series
+                raise ValueError("Too many indices")
             if self.ndim == 1 or not any(isinstance(x, slice) for x in tup):
                 # GH#10521 Series should reduce MultiIndex dimensions instead of
                 #  DataFrame, IndexingError is not raised when slice(None,None,None)
@@ -1203,6 +1208,11 @@ def _convert_to_indexer(self, key, axis: int, is_setter: bool = False):
             return {"key": key}
 
         if is_nested_tuple(key, labels):
+            if isinstance(self.obj, ABCSeries) and any(
+                isinstance(k, tuple) for k in key
+            ):
+                # GH#35349 Raise if tuple in tuple for series
+                raise ValueError("Too many indices")
             return labels.get_locs(key)
 
         elif is_list_like_indexer(key):
diff --git a/pandas/tests/indexing/test_loc.py b/pandas/tests/indexing/test_loc.py
index aec5e3adfe111..b6e4c38ef7f0e 100644
--- a/pandas/tests/indexing/test_loc.py
+++ b/pandas/tests/indexing/test_loc.py
@@ -17,6 +17,7 @@
     DataFrame,
     DatetimeIndex,
     Index,
+    IndexSlice,
     MultiIndex,
     Series,
     SparseDtype,
@@ -2130,3 +2131,17 @@ def test_loc_iloc_setitem_with_listlike(self, size, array_fn):
         ser = Series(0, index=list("abcde"), dtype=object)
         ser.iloc[0] = arr
         tm.assert_series_equal(ser, expected)
+
+    @pytest.mark.parametrize("indexer", [IndexSlice["A", :], ("A", slice(None))])
+    def test_loc_series_getitem_too_many_dimensions(self, indexer):
+        # GH#35349
+        ser = Series(
+            index=MultiIndex.from_tuples([("A", "0"), ("A", "1"), ("B", "0")]),
+            data=[21, 22, 23],
+        )
+        msg = "Too many indices"
+        with pytest.raises(ValueError, match=msg):
+            ser.loc[indexer, :]
+
+        with pytest.raises(ValueError, match=msg):
+            ser.loc[indexer, :] = 1