diff --git a/doc/source/whatsnew/v2.1.0.rst b/doc/source/whatsnew/v2.1.0.rst
index 6a0470b839843..ee1f1b7be1b86 100644
--- a/doc/source/whatsnew/v2.1.0.rst
+++ b/doc/source/whatsnew/v2.1.0.rst
@@ -495,6 +495,7 @@ Reshaping
 - Bug in :func:`crosstab` when ``dropna=False`` would not keep ``np.nan`` in the result (:issue:`10772`)
 - Bug in :func:`merge_asof` raising ``KeyError`` for extension dtypes (:issue:`52904`)
 - Bug in :func:`merge_asof` raising ``ValueError`` for data backed by read-only ndarrays (:issue:`53513`)
+- Bug in :func:`merge_asof` with ``left_index=True`` or ``right_index=True`` with mismatched index dtypes giving incorrect results in some cases instead of raising ``MergeError`` (:issue:`53870`)
 - Bug in :meth:`DataFrame.agg` and :meth:`Series.agg` on non-unique columns would return incorrect type when dist-like argument passed in (:issue:`51099`)
 - Bug in :meth:`DataFrame.combine_first` ignoring other's columns if ``other`` is empty (:issue:`53792`)
 - Bug in :meth:`DataFrame.idxmin` and :meth:`DataFrame.idxmax`, where the axis dtype would be lost for empty frames (:issue:`53265`)
@@ -503,6 +504,7 @@ Reshaping
 - Bug in :meth:`DataFrame.stack` sorting columns lexicographically (:issue:`53786`)
 - Bug in :meth:`DataFrame.transpose` inferring dtype for object column (:issue:`51546`)
 - Bug in :meth:`Series.combine_first` converting ``int64`` dtype to ``float64`` and losing precision on very large integers (:issue:`51764`)
+-
 
 Sparse
 ^^^^^^
diff --git a/pandas/core/reshape/merge.py b/pandas/core/reshape/merge.py
index 200e67aee80cc..e68277c38063e 100644
--- a/pandas/core/reshape/merge.py
+++ b/pandas/core/reshape/merge.py
@@ -1992,11 +1992,10 @@ def _maybe_require_matching_dtypes(
     ) -> None:
         # TODO: why do we do this for AsOfMerge but not the others?
 
-        # validate index types are the same
-        for i, (lk, rk) in enumerate(zip(left_join_keys, right_join_keys)):
-            if lk.dtype != rk.dtype:
-                if isinstance(lk.dtype, CategoricalDtype) and isinstance(
-                    rk.dtype, CategoricalDtype
+        def _check_dtype_match(left: ArrayLike, right: ArrayLike, i: int):
+            if left.dtype != right.dtype:
+                if isinstance(left.dtype, CategoricalDtype) and isinstance(
+                    right.dtype, CategoricalDtype
                 ):
                     # The generic error message is confusing for categoricals.
                     #
@@ -2007,16 +2006,32 @@ def _maybe_require_matching_dtypes(
                     # later with a ValueError, so we don't *need* to check
                     # for them here.
                     msg = (
-                        f"incompatible merge keys [{i}] {repr(lk.dtype)} and "
-                        f"{repr(rk.dtype)}, both sides category, but not equal ones"
+                        f"incompatible merge keys [{i}] {repr(left.dtype)} and "
+                        f"{repr(right.dtype)}, both sides category, but not equal ones"
                     )
                 else:
                     msg = (
-                        f"incompatible merge keys [{i}] {repr(lk.dtype)} and "
-                        f"{repr(rk.dtype)}, must be the same type"
+                        f"incompatible merge keys [{i}] {repr(left.dtype)} and "
+                        f"{repr(right.dtype)}, must be the same type"
                     )
                 raise MergeError(msg)
 
+        # validate index types are the same
+        for i, (lk, rk) in enumerate(zip(left_join_keys, right_join_keys)):
+            _check_dtype_match(lk, rk, i)
+
+        if self.left_index:
+            lt = self.left.index._values
+        else:
+            lt = left_join_keys[-1]
+
+        if self.right_index:
+            rt = self.right.index._values
+        else:
+            rt = right_join_keys[-1]
+
+        _check_dtype_match(lt, rt, 0)
+
     def _validate_tolerance(self, left_join_keys: list[ArrayLike]) -> None:
         # validate tolerance; datetime.timedelta or Timedelta if we have a DTI
         if self.tolerance is not None:
@@ -2090,6 +2105,10 @@ def injection(obj: ArrayLike):
         right_values = (
             self.right.index._values if self.right_index else self.right_join_keys[-1]
         )
+
+        # _maybe_require_matching_dtypes already checked for dtype matching
+        assert left_values.dtype == right_values.dtype
+
         tolerance = self.tolerance
 
         # we require sortedness and non-null values in the join keys
diff --git a/pandas/tests/reshape/merge/test_merge_asof.py b/pandas/tests/reshape/merge/test_merge_asof.py
index 0678074943ffb..67591b2adc2f9 100644
--- a/pandas/tests/reshape/merge/test_merge_asof.py
+++ b/pandas/tests/reshape/merge/test_merge_asof.py
@@ -418,6 +418,34 @@ def test_multiby_heterogeneous_types(self):
         result = merge_asof(trades, quotes, on="time", by=["ticker", "exch"])
         tm.assert_frame_equal(result, expected)
 
+    def test_mismatched_index_dtype(self):
+        # similar to test_multiby_indexed, but we change the dtype on left.index
+        left = pd.DataFrame(
+            [
+                [to_datetime("20160602"), 1, "a"],
+                [to_datetime("20160602"), 2, "a"],
+                [to_datetime("20160603"), 1, "b"],
+                [to_datetime("20160603"), 2, "b"],
+            ],
+            columns=["time", "k1", "k2"],
+        ).set_index("time")
+        # different dtype for the index
+        left.index = left.index - pd.Timestamp(0)
+
+        right = pd.DataFrame(
+            [
+                [to_datetime("20160502"), 1, "a", 1.0],
+                [to_datetime("20160502"), 2, "a", 2.0],
+                [to_datetime("20160503"), 1, "b", 3.0],
+                [to_datetime("20160503"), 2, "b", 4.0],
+            ],
+            columns=["time", "k1", "k2", "value"],
+        ).set_index("time")
+
+        msg = "incompatible merge keys"
+        with pytest.raises(MergeError, match=msg):
+            merge_asof(left, right, left_index=True, right_index=True, by=["k1", "k2"])
+
     def test_multiby_indexed(self):
         # GH15676
         left = pd.DataFrame(