diff --git a/pandas/core/internals/blocks.py b/pandas/core/internals/blocks.py
index 75c935cdf2e60..80573f32b936e 100644
--- a/pandas/core/internals/blocks.py
+++ b/pandas/core/internals/blocks.py
@@ -8,7 +8,7 @@
 
 from pandas._libs import NaT, algos as libalgos, lib, writers
 import pandas._libs.internals as libinternals
-from pandas._libs.tslibs import Timedelta, conversion
+from pandas._libs.tslibs import conversion
 from pandas._libs.tslibs.timezones import tz_compare
 from pandas._typing import ArrayLike
 from pandas.util._validators import validate_bool_kwarg
diff --git a/pandas/core/internals/managers.py b/pandas/core/internals/managers.py
index b8f45523106b3..fcde8d12d1609 100644
--- a/pandas/core/internals/managers.py
+++ b/pandas/core/internals/managers.py
@@ -7,14 +7,13 @@
 
 import numpy as np
 
-from pandas._libs import Timedelta, Timestamp, internals as libinternals, lib
+from pandas._libs import internals as libinternals, lib
 from pandas._typing import ArrayLike, DtypeObj, Label, Scalar
 from pandas.util._validators import validate_bool_kwarg
 
 from pandas.core.dtypes.cast import (
     find_common_type,
     infer_dtype_from_scalar,
-    maybe_convert_objects,
     maybe_promote,
 )
 from pandas.core.dtypes.common import (
@@ -33,6 +32,7 @@
 import pandas.core.algorithms as algos
 from pandas.core.arrays.sparse import SparseDtype
 from pandas.core.base import PandasObject
+import pandas.core.common as com
 from pandas.core.construction import extract_array
 from pandas.core.indexers import maybe_convert_indices
 from pandas.core.indexes.api import Index, ensure_index
@@ -626,11 +626,8 @@ def comp(s, regex=False):
             """
             if isna(s):
                 return isna(values)
-            if isinstance(s, (Timedelta, Timestamp)) and getattr(s, "tz", None) is None:
 
-                return _compare_or_regex_search(
-                    maybe_convert_objects(values), s.asm8, regex
-                )
+            s = com.maybe_box_datetimelike(s)
             return _compare_or_regex_search(values, s, regex)
 
         masks = [comp(s, regex) for s in src_list]
@@ -643,11 +640,10 @@ def comp(s, regex=False):
             # replace ALWAYS will return a list
             rb = [blk if inplace else blk.copy()]
             for i, (s, d) in enumerate(zip(src_list, dest_list)):
-                # TODO: assert/validate that `d` is always a scalar?
                 new_rb: List[Block] = []
                 for b in rb:
                     m = masks[i][b.mgr_locs.indexer]
-                    convert = i == src_len
+                    convert = i == src_len  # only convert once at the end
                     result = b._replace_coerce(
                         mask=m,
                         to_replace=s,
diff --git a/pandas/tests/series/methods/test_replace.py b/pandas/tests/series/methods/test_replace.py
index 685457aff6341..1c54e2b988219 100644
--- a/pandas/tests/series/methods/test_replace.py
+++ b/pandas/tests/series/methods/test_replace.py
@@ -108,6 +108,16 @@ def test_replace_gh5319(self):
         expected = pd.Series([pd.Timestamp.min, ts], dtype=object)
         tm.assert_series_equal(expected, result)
 
+    def test_replace_timedelta_td64(self):
+        tdi = pd.timedelta_range(0, periods=5)
+        ser = pd.Series(tdi)
+
+        # Using a single dict argument means we go through replace_list
+        result = ser.replace({ser[1]: ser[3]})
+
+        expected = pd.Series([ser[0], ser[3], ser[2], ser[3], ser[4]])
+        tm.assert_series_equal(result, expected)
+
     def test_replace_with_single_list(self):
         ser = pd.Series([0, 1, 2, 3, 4])
         result = ser.replace([1, 2, 3])