diff --git a/pandas/_libs/tslibs/timestamps.pyi b/pandas/_libs/tslibs/timestamps.pyi
index e4be7fda43005..8382fe0274138 100644
--- a/pandas/_libs/tslibs/timestamps.pyi
+++ b/pandas/_libs/tslibs/timestamps.pyi
@@ -27,6 +27,7 @@ _DatetimeT = TypeVar("_DatetimeT", bound=datetime)
 def integer_op_not_supported(obj: object) -> TypeError: ...
 
 class Timestamp(datetime):
+    _reso: int
     min: ClassVar[Timestamp]
     max: ClassVar[Timestamp]
 
diff --git a/pandas/core/arrays/datetimelike.py b/pandas/core/arrays/datetimelike.py
index 848d2f879fbf2..6999d7168622c 100644
--- a/pandas/core/arrays/datetimelike.py
+++ b/pandas/core/arrays/datetimelike.py
@@ -1209,6 +1209,14 @@ def _sub_datetimelike_scalar(self, other: datetime | np.datetime64):
             return self - NaT
 
         other = Timestamp(other)
+
+        if other._reso != self._reso:
+            if other._reso < self._reso:
+                other = other._as_unit(self._unit)
+            else:
+                unit = npy_unit_to_abbrev(other._reso)
+                self = self._as_unit(unit)
+
         return self._sub_datetimelike(other)
 
     @final
@@ -1221,6 +1229,13 @@ def _sub_datetime_arraylike(self, other):
 
         self = cast("DatetimeArray", self)
         other = ensure_wrapped_if_datetimelike(other)
+
+        if other._reso != self._reso:
+            if other._reso < self._reso:
+                other = other._as_unit(self._unit)
+            else:
+                self = self._as_unit(other._unit)
+
         return self._sub_datetimelike(other)
 
     @final
diff --git a/pandas/tests/arrays/test_datetimes.py b/pandas/tests/arrays/test_datetimes.py
index 83850c6cd2594..8c2a8df7c2fbd 100644
--- a/pandas/tests/arrays/test_datetimes.py
+++ b/pandas/tests/arrays/test_datetimes.py
@@ -13,7 +13,10 @@
 
 import pandas as pd
 import pandas._testing as tm
-from pandas.core.arrays import DatetimeArray
+from pandas.core.arrays import (
+    DatetimeArray,
+    TimedeltaArray,
+)
 
 
 class TestNonNano:
@@ -218,6 +221,32 @@ def test_add_mismatched_reso_doesnt_downcast(self):
         #  (so we _could_ downcast to unit="s"), we do not.
         assert res._unit == "us"
 
+    def test_sub_datetimelike_scalar_mismatch(self):
+        dti = pd.date_range("2016-01-01", periods=3)
+        dta = dti._data._as_unit("us")
+
+        ts = dta[0]._as_unit("s")
+
+        result = dta - ts
+        expected = (dti - dti[0])._data._as_unit("us")
+        assert result.dtype == "m8[us]"
+        tm.assert_extension_array_equal(result, expected)
+
+    def test_sub_datetime64_reso_mismatch(self):
+        dti = pd.date_range("2016-01-01", periods=3)
+        left = dti._data._as_unit("s")
+        right = left._as_unit("ms")
+
+        result = left - right
+        exp_values = np.array([0, 0, 0], dtype="m8[ms]")
+        expected = TimedeltaArray._simple_new(
+            exp_values,
+            dtype=exp_values.dtype,
+        )
+        tm.assert_extension_array_equal(result, expected)
+        result2 = right - left
+        tm.assert_extension_array_equal(result2, expected)
+
 
 class TestDatetimeArrayComparisons:
     # TODO: merge this into tests/arithmetic/test_datetime64 once it is