diff --git a/doc/source/whatsnew/v0.25.0.rst b/doc/source/whatsnew/v0.25.0.rst
index 8dabaeb6c7bfe..4de9854330bc0 100644
--- a/doc/source/whatsnew/v0.25.0.rst
+++ b/doc/source/whatsnew/v0.25.0.rst
@@ -283,6 +283,7 @@ Timezones
 - Bug in :func:`Timestamp.tz_localize` and :func:`Timestamp.tz_convert` does not propagate ``freq`` (:issue:`25241`)
 - Bug in :func:`Series.at` where setting :class:`Timestamp` with timezone raises ``TypeError`` (:issue:`25506`)
 - Bug in :func:`DataFrame.update` when updating with timezone aware data would return timezone naive data (:issue:`25807`)
+- Bug in :func:`to_datetime` where an uninformative ``RuntimeError`` was raised when passing a naive :class:`Timestamp` with datetime strings with mixed UTC offsets (:issue:`25978`)
 
 Numeric
 ^^^^^^^
diff --git a/pandas/_libs/tslib.pyx b/pandas/_libs/tslib.pyx
index 5f0c2c9659b35..d0ae15e28bb4d 100644
--- a/pandas/_libs/tslib.pyx
+++ b/pandas/_libs/tslib.pyx
@@ -792,7 +792,8 @@ cdef array_to_datetime_object(ndarray[object] values, bint is_raise,
     # 2) datetime strings, which we return as datetime.datetime
     for i in range(n):
         val = values[i]
-        if checknull_with_nat(val):
+        if checknull_with_nat(val) or PyDateTime_Check(val):
+            # GH 25978. No need to parse NaT-like or datetime-like vals
             oresult[i] = val
         elif isinstance(val, str):
             if len(val) == 0 or val in nat_strings:
diff --git a/pandas/tests/indexes/datetimes/test_tools.py b/pandas/tests/indexes/datetimes/test_tools.py
index 4d4ad151173b1..eaf689cfa1c21 100644
--- a/pandas/tests/indexes/datetimes/test_tools.py
+++ b/pandas/tests/indexes/datetimes/test_tools.py
@@ -762,7 +762,7 @@ def test_iso_8601_strings_with_different_offsets(self):
                                   NaT], tz='UTC')
         tm.assert_index_equal(result, expected)
 
-    def test_iss8601_strings_mixed_offsets_with_naive(self):
+    def test_iso8601_strings_mixed_offsets_with_naive(self):
         # GH 24992
         result = pd.to_datetime([
             '2018-11-28T00:00:00',
@@ -785,6 +785,18 @@ def test_iss8601_strings_mixed_offsets_with_naive(self):
         expected = pd.to_datetime(list(reversed(items)), utc=True)[::-1]
         tm.assert_index_equal(result, expected)
 
+    def test_mixed_offsets_with_native_datetime_raises(self):
+        # GH 25978
+        s = pd.Series([
+            'nan',
+            pd.Timestamp("1990-01-01"),
+            "2015-03-14T16:15:14.123-08:00",
+            "2019-03-04T21:56:32.620-07:00",
+            None,
+        ])
+        with pytest.raises(ValueError, match="Tz-aware datetime.datetime"):
+            pd.to_datetime(s)
+
     def test_non_iso_strings_with_tz_offset(self):
         result = to_datetime(['March 1, 2018 12:00:00+0400'] * 2)
         expected = DatetimeIndex([datetime(2018, 3, 1, 12,