diff --git a/doc/source/whatsnew/v1.0.0.rst b/doc/source/whatsnew/v1.0.0.rst
index b02769322e013..173cc6b6b483c 100644
--- a/doc/source/whatsnew/v1.0.0.rst
+++ b/doc/source/whatsnew/v1.0.0.rst
@@ -180,7 +180,8 @@ Datetimelike
 - Addition and subtraction of integer or integer-dtype arrays with :class:`Timestamp` will now raise ``NullFrequencyError`` instead of ``ValueError`` (:issue:`28268`)
 - Bug in :class:`Series` and :class:`DataFrame` with integer dtype failing to raise ``TypeError`` when adding or subtracting a ``np.datetime64`` object (:issue:`28080`)
 - Bug in :class:`Week` with ``weekday`` incorrectly raising ``AttributeError`` instead of ``TypeError`` when adding or subtracting an invalid type (:issue:`28530`)
-
+- Bug in :class:`DataFrame` arithmetic operations when operating with a :class:`Series` with dtype `'timedelta64[ns]'` (:issue:`28049`)
+-
 
 Timedelta
 ^^^^^^^^^
diff --git a/pandas/core/ops/__init__.py b/pandas/core/ops/__init__.py
index ca4f35514f2a5..f53b5045abff3 100644
--- a/pandas/core/ops/__init__.py
+++ b/pandas/core/ops/__init__.py
@@ -498,8 +498,19 @@ def column_op(a, b):
         # in which case we specifically want to operate row-by-row
         assert right.index.equals(left.columns)
 
-        def column_op(a, b):
-            return {i: func(a.iloc[:, i], b.iloc[i]) for i in range(len(a.columns))}
+        if right.dtype == "timedelta64[ns]":
+            # ensure we treat NaT values as the correct dtype
+            # Note: we do not do this unconditionally as it may be lossy or
+            #  expensive for EA dtypes.
+            right = np.asarray(right)
+
+            def column_op(a, b):
+                return {i: func(a.iloc[:, i], b[i]) for i in range(len(a.columns))}
+
+        else:
+
+            def column_op(a, b):
+                return {i: func(a.iloc[:, i], b.iloc[i]) for i in range(len(a.columns))}
 
     elif isinstance(right, ABCSeries):
         assert right.index.equals(left.index)  # Handle other cases later
diff --git a/pandas/tests/frame/test_arithmetic.py b/pandas/tests/frame/test_arithmetic.py
index 706bc122c6d9e..fc3640503e385 100644
--- a/pandas/tests/frame/test_arithmetic.py
+++ b/pandas/tests/frame/test_arithmetic.py
@@ -457,6 +457,16 @@ def test_arith_flex_zero_len_raises(self):
 
 
 class TestFrameArithmetic:
+    def test_td64_op_nat_casting(self):
+        # Make sure we don't accidentally treat timedelta64(NaT) as datetime64
+        #  when calling dispatch_to_series in DataFrame arithmetic
+        ser = pd.Series(["NaT", "NaT"], dtype="timedelta64[ns]")
+        df = pd.DataFrame([[1, 2], [3, 4]])
+
+        result = df * ser
+        expected = pd.DataFrame({0: ser, 1: ser})
+        tm.assert_frame_equal(result, expected)
+
     def test_df_add_2d_array_rowlike_broadcasts(self):
         # GH#23000
         arr = np.arange(6).reshape(3, 2)