diff --git a/doc/source/whatsnew/v1.5.1.rst b/doc/source/whatsnew/v1.5.1.rst
index 3f4265245bcb6..c998b2ce99628 100644
--- a/doc/source/whatsnew/v1.5.1.rst
+++ b/doc/source/whatsnew/v1.5.1.rst
@@ -14,6 +14,7 @@ including other versions of pandas.
 
 Fixed regressions
 ~~~~~~~~~~~~~~~~~
+- Fixed Regression in :meth:`Series.__setitem__` casting ``None`` to ``NaN`` for object dtype (:issue:`48665`)
 - Fixed Regression in :meth:`DataFrame.loc` when setting values as a :class:`DataFrame` with all ``True`` indexer (:issue:`48701`)
 - Regression in :func:`.read_csv` causing an ``EmptyDataError`` when using an UTF-8 file handle that was already read from (:issue:`48646`)
 - Fixed performance regression in :func:`factorize` when ``na_sentinel`` is not ``None`` and ``sort=False`` (:issue:`48620`)
diff --git a/pandas/core/indexing.py b/pandas/core/indexing.py
index bca8b3d459245..591ab9630ebb5 100644
--- a/pandas/core/indexing.py
+++ b/pandas/core/indexing.py
@@ -2112,9 +2112,14 @@ def _setitem_with_indexer_missing(self, indexer, value):
             # this preserves dtype of the value and of the object
             if not is_scalar(value):
                 new_dtype = None
+
             elif is_valid_na_for_dtype(value, self.obj.dtype):
-                value = na_value_for_dtype(self.obj.dtype, compat=False)
+                if not is_object_dtype(self.obj.dtype):
+                    # Every NA value is suitable for object, no conversion needed
+                    value = na_value_for_dtype(self.obj.dtype, compat=False)
+
                 new_dtype = maybe_promote(self.obj.dtype, value)[0]
+
             elif isna(value):
                 new_dtype = None
             elif not self.obj.empty and not is_object_dtype(self.obj.dtype):
diff --git a/pandas/tests/series/indexing/test_setitem.py b/pandas/tests/series/indexing/test_setitem.py
index 90051405c6935..9ab3b6ead017f 100644
--- a/pandas/tests/series/indexing/test_setitem.py
+++ b/pandas/tests/series/indexing/test_setitem.py
@@ -562,6 +562,14 @@ def test_setitem_enlarge_with_na(self, na, target_na, dtype, target_dtype, index
         expected = Series(expected_values, dtype=target_dtype)
         tm.assert_series_equal(ser, expected)
 
+    def test_setitem_enlargement_object_none(self, nulls_fixture):
+        # GH#48665
+        ser = Series(["a", "b"])
+        ser[3] = nulls_fixture
+        expected = Series(["a", "b", nulls_fixture], index=[0, 1, 3])
+        tm.assert_series_equal(ser, expected)
+        assert ser[3] is nulls_fixture
+
 
 def test_setitem_scalar_into_readonly_backing_data():
     # GH#14359: test that you cannot mutate a read only buffer