diff --git a/pandas/core/arrays/datetimelike.py b/pandas/core/arrays/datetimelike.py
index 410995d8dec53..7e4ce970d1b9c 100644
--- a/pandas/core/arrays/datetimelike.py
+++ b/pandas/core/arrays/datetimelike.py
@@ -866,6 +866,10 @@ def isin(self, values) -> npt.NDArray[np.bool_]:
             except ValueError:
                 return isin(self.astype(object), values)
 
+        if self.dtype.kind in ["m", "M"]:
+            self = cast("DatetimeArray | TimedeltaArray", self)
+            values = values._as_unit(self._unit)
+
         try:
             self._check_compatible_with(values)
         except (TypeError, ValueError):
diff --git a/pandas/tests/series/methods/test_isin.py b/pandas/tests/series/methods/test_isin.py
index 2288dfb5c2409..0eca3e0512849 100644
--- a/pandas/tests/series/methods/test_isin.py
+++ b/pandas/tests/series/methods/test_isin.py
@@ -43,6 +43,33 @@ def test_isin_with_string_scalar(self):
         with pytest.raises(TypeError, match=msg):
             s.isin("aaa")
 
+    def test_isin_datetimelike_mismatched_reso(self):
+        expected = Series([True, True, False, False, False])
+
+        ser = Series(date_range("jan-01-2013", "jan-05-2013"))
+
+        # fails on dtype conversion in the first place
+        day_values = np.asarray(ser[0:2].values).astype("datetime64[D]")
+        result = ser.isin(day_values)
+        tm.assert_series_equal(result, expected)
+
+        dta = ser[:2]._values.astype("M8[s]")
+        result = ser.isin(dta)
+        tm.assert_series_equal(result, expected)
+
+    @pytest.mark.xfail(
+        reason="DTA._from_sequence incorrectly treats Timestamp[s].value as "
+        "nanoseconds."
+    )
+    def test_isin_datetimelike_mismatched_reso_list(self):
+        expected = Series([True, True, False, False, False])
+
+        ser = Series(date_range("jan-01-2013", "jan-05-2013"))
+
+        dta = ser[:2]._values.astype("M8[s]")
+        result = ser.isin(list(dta))
+        tm.assert_series_equal(result, expected)
+
     def test_isin_with_i8(self):
         # GH#5021
 
@@ -58,10 +85,6 @@ def test_isin_with_i8(self):
         result = s.isin(s[0:2].values)
         tm.assert_series_equal(result, expected)
 
-        # fails on dtype conversion in the first place
-        result = s.isin(np.asarray(s[0:2].values).astype("datetime64[D]"))
-        tm.assert_series_equal(result, expected)
-
         result = s.isin([s[1]])
         tm.assert_series_equal(result, expected2)