diff --git a/doc/source/whatsnew/v1.3.0.rst b/doc/source/whatsnew/v1.3.0.rst
index d24c595cacab5..5ab183ed81740 100644
--- a/doc/source/whatsnew/v1.3.0.rst
+++ b/doc/source/whatsnew/v1.3.0.rst
@@ -335,6 +335,7 @@ Indexing
 - Bug in :meth:`DataFrame.__getitem__` and :meth:`Series.__getitem__` always raising ``KeyError`` when slicing with existing strings an :class:`Index` with milliseconds (:issue:`33589`)
 - Bug in setting ``timedelta64`` values into numeric :class:`Series` failing to cast to object dtype (:issue:`39086`)
 - Bug in setting :class:`Interval` values into a :class:`Series` or :class:`DataFrame` with mismatched :class:`IntervalDtype` incorrectly casting the new values to the existing dtype (:issue:`39120`)
+- Bug in setting ``datetime64`` values into a :class:`Series` with integer-dtype incorrect casting the datetime64 values to integers (:issue:`39266`)
 - Bug in incorrectly raising in :meth:`Index.insert`, when setting a new column that cannot be held in the existing ``frame.columns``, or in :meth:`Series.reset_index` or :meth:`DataFrame.reset_index` instead of casting to a compatible dtype (:issue:`39068`)
 
 Missing
diff --git a/pandas/core/internals/blocks.py b/pandas/core/internals/blocks.py
index fe5256ca42982..eb8bb0fe90e9a 100644
--- a/pandas/core/internals/blocks.py
+++ b/pandas/core/internals/blocks.py
@@ -968,8 +968,18 @@ def setitem(self, indexer, value):
                 # TODO(EA2D): special case not needed with 2D EA
                 values[indexer] = value.to_numpy(values.dtype).reshape(-1, 1)
 
-        # set
+        elif self.is_object and not is_ea_value and arr_value.dtype.kind in ["m", "M"]:
+            # https://github.com/numpy/numpy/issues/12550
+            #  numpy will incorrect cast to int if we're not careful
+            if is_list_like(value):
+                value = list(value)
+            else:
+                value = [value] * len(values[indexer])
+
+            values[indexer] = value
+
         else:
+
             values[indexer] = value
 
         if transpose:
diff --git a/pandas/tests/series/indexing/test_setitem.py b/pandas/tests/series/indexing/test_setitem.py
index 06a1beffc3a68..f08b1511c455c 100644
--- a/pandas/tests/series/indexing/test_setitem.py
+++ b/pandas/tests/series/indexing/test_setitem.py
@@ -257,6 +257,27 @@ def test_setitem_callable_other(self):
         tm.assert_series_equal(ser, expected)
 
 
+class TestSetitemCasting:
+    @pytest.mark.parametrize("dtype", ["M8[ns]", "m8[ns]"])
+    def test_setitem_dt64_into_int_series(self, dtype):
+        # dont cast dt64 to int when doing this setitem
+        orig = Series([1, 2, 3])
+
+        val = np.datetime64("2021-01-18 13:25:00", "ns")
+        if dtype == "m8[ns]":
+            val = val - val
+
+        ser = orig.copy()
+        ser[:-1] = val
+        expected = Series([val, val, 3], dtype=object)
+        tm.assert_series_equal(ser, expected)
+        assert isinstance(ser[0], type(val))
+
+        ser = orig.copy()
+        ser[:-1] = np.array([val, val])
+        tm.assert_series_equal(ser, expected)
+
+
 @pytest.mark.parametrize(
     "obj,expected,key",
     [