diff --git a/doc/source/whatsnew/v2.2.1.rst b/doc/source/whatsnew/v2.2.1.rst
index 85b9346aa01a5..ab62a7c7598d5 100644
--- a/doc/source/whatsnew/v2.2.1.rst
+++ b/doc/source/whatsnew/v2.2.1.rst
@@ -42,6 +42,7 @@ Fixed regressions
 - Fixed regression in :meth:`Series.astype` introducing decimals when converting from integer with missing values to string dtype (:issue:`57418`)
 - Fixed regression in :meth:`Series.pct_change` raising a ``ValueError`` for an empty :class:`Series` (:issue:`57056`)
 - Fixed regression in :meth:`Series.to_numpy` when dtype is given as float and the data contains NaNs (:issue:`57121`)
+- Fixed regression in addition or subtraction of :class:`DateOffset` objects with millisecond components to ``datetime64`` :class:`Index`, :class:`Series`, or :class:`DataFrame` (:issue:`57529`)
 
 .. ---------------------------------------------------------------------------
 .. _whatsnew_221.bug_fixes:
diff --git a/pandas/_libs/tslibs/offsets.pyx b/pandas/_libs/tslibs/offsets.pyx
index 70e1ca1c4012a..c37a4b285daef 100644
--- a/pandas/_libs/tslibs/offsets.pyx
+++ b/pandas/_libs/tslibs/offsets.pyx
@@ -1458,13 +1458,22 @@ cdef class RelativeDeltaOffset(BaseOffset):
             "minutes",
             "seconds",
             "microseconds",
+            "milliseconds",
         }
         # relativedelta/_offset path only valid for base DateOffset
         if self._use_relativedelta and set(kwds).issubset(relativedelta_fast):
+            td_args = {
+                "days",
+                "hours",
+                "minutes",
+                "seconds",
+                "microseconds",
+                "milliseconds"
+            }
             td_kwds = {
                 key: val
                 for key, val in kwds.items()
-                if key in ["days", "hours", "minutes", "seconds", "microseconds"]
+                if key in td_args
             }
             if "weeks" in kwds:
                 days = td_kwds.get("days", 0)
@@ -1474,6 +1483,8 @@ cdef class RelativeDeltaOffset(BaseOffset):
                 delta = Timedelta(**td_kwds)
                 if "microseconds" in kwds:
                     delta = delta.as_unit("us")
+                elif "milliseconds" in kwds:
+                    delta = delta.as_unit("ms")
                 else:
                     delta = delta.as_unit("s")
             else:
@@ -1491,6 +1502,8 @@ cdef class RelativeDeltaOffset(BaseOffset):
                 delta = Timedelta(self._offset * self.n)
                 if "microseconds" in kwds:
                     delta = delta.as_unit("us")
+                elif "milliseconds" in kwds:
+                    delta = delta.as_unit("ms")
                 else:
                     delta = delta.as_unit("s")
             return delta
diff --git a/pandas/tests/arithmetic/test_datetime64.py b/pandas/tests/arithmetic/test_datetime64.py
index dbff88dc6f4f6..a468449efd507 100644
--- a/pandas/tests/arithmetic/test_datetime64.py
+++ b/pandas/tests/arithmetic/test_datetime64.py
@@ -1586,6 +1586,38 @@ def test_dti_add_sub_nonzero_mth_offset(
         expected = tm.box_expected(expected, box_with_array, False)
         tm.assert_equal(result, expected)
 
+    def test_dt64arr_series_add_DateOffset_with_milli(self):
+        # GH 57529
+        dti = DatetimeIndex(
+            [
+                "2000-01-01 00:00:00.012345678",
+                "2000-01-31 00:00:00.012345678",
+                "2000-02-29 00:00:00.012345678",
+            ],
+            dtype="datetime64[ns]",
+        )
+        result = dti + DateOffset(milliseconds=4)
+        expected = DatetimeIndex(
+            [
+                "2000-01-01 00:00:00.016345678",
+                "2000-01-31 00:00:00.016345678",
+                "2000-02-29 00:00:00.016345678",
+            ],
+            dtype="datetime64[ns]",
+        )
+        tm.assert_index_equal(result, expected)
+
+        result = dti + DateOffset(days=1, milliseconds=4)
+        expected = DatetimeIndex(
+            [
+                "2000-01-02 00:00:00.016345678",
+                "2000-02-01 00:00:00.016345678",
+                "2000-03-01 00:00:00.016345678",
+            ],
+            dtype="datetime64[ns]",
+        )
+        tm.assert_index_equal(result, expected)
+
 
 class TestDatetime64OverflowHandling:
     # TODO: box + de-duplicate