diff --git a/doc/source/whatsnew/v1.3.5.rst b/doc/source/whatsnew/v1.3.5.rst
index 951b05b65c81b..34e67e51e47e3 100644
--- a/doc/source/whatsnew/v1.3.5.rst
+++ b/doc/source/whatsnew/v1.3.5.rst
@@ -15,6 +15,7 @@ including other versions of pandas.
 Fixed regressions
 ~~~~~~~~~~~~~~~~~
 - Fixed regression in :meth:`Series.equals` when comparing floats with dtype object to None (:issue:`44190`)
+- Fixed regression in :func:`merge_asof` raising error when array was supplied as join key (:issue:`42844`)
 - Fixed performance regression in :func:`read_csv` (:issue:`44106`)
 - Fixed regression in :meth:`Series.duplicated` and :meth:`Series.drop_duplicates` when Series has :class:`Categorical` dtype with boolean categories (:issue:`44351`)
 -
diff --git a/pandas/core/reshape/merge.py b/pandas/core/reshape/merge.py
index 55d8dfa94f89e..c767cf59a44a1 100644
--- a/pandas/core/reshape/merge.py
+++ b/pandas/core/reshape/merge.py
@@ -1781,21 +1781,27 @@ def _validate_specification(self) -> None:
         # GH#29130 Check that merge keys do not have dtype object
         if not self.left_index:
             left_on = self.left_on[0]
-            lo_dtype = (
-                self.left[left_on].dtype
-                if left_on in self.left.columns
-                else self.left.index.get_level_values(left_on)
-            )
+            if is_array_like(left_on):
+                lo_dtype = left_on.dtype
+            else:
+                lo_dtype = (
+                    self.left[left_on].dtype
+                    if left_on in self.left.columns
+                    else self.left.index.get_level_values(left_on)
+                )
         else:
             lo_dtype = self.left.index.dtype
 
         if not self.right_index:
             right_on = self.right_on[0]
-            ro_dtype = (
-                self.right[right_on].dtype
-                if right_on in self.right.columns
-                else self.right.index.get_level_values(right_on)
-            )
+            if is_array_like(right_on):
+                ro_dtype = right_on.dtype
+            else:
+                ro_dtype = (
+                    self.right[right_on].dtype
+                    if right_on in self.right.columns
+                    else self.right.index.get_level_values(right_on)
+                )
         else:
             ro_dtype = self.right.index.dtype
 
diff --git a/pandas/tests/reshape/merge/test_merge_asof.py b/pandas/tests/reshape/merge/test_merge_asof.py
index 310cf2debadc6..6582a234fd263 100644
--- a/pandas/tests/reshape/merge/test_merge_asof.py
+++ b/pandas/tests/reshape/merge/test_merge_asof.py
@@ -1484,3 +1484,44 @@ def test_merge_asof_numeri_column_in_index_object_dtype():
         match=r"Incompatible merge dtype, .*, both sides must have numeric dtype",
     ):
         merge_asof(left, right, left_on="a", right_on="a")
+
+
+def test_merge_asof_array_as_on():
+    # GH#42844
+    right = pd.DataFrame(
+        {
+            "a": [2, 6],
+            "ts": [pd.Timestamp("2021/01/01 00:37"), pd.Timestamp("2021/01/01 01:40")],
+        }
+    )
+    ts_merge = pd.date_range(
+        start=pd.Timestamp("2021/01/01 00:00"), periods=3, freq="1h"
+    )
+    left = pd.DataFrame({"b": [4, 8, 7]})
+    result = merge_asof(
+        left,
+        right,
+        left_on=ts_merge,
+        right_on="ts",
+        allow_exact_matches=False,
+        direction="backward",
+    )
+    expected = pd.DataFrame({"b": [4, 8, 7], "a": [np.nan, 2, 6], "ts": ts_merge})
+    tm.assert_frame_equal(result, expected)
+
+    result = merge_asof(
+        right,
+        left,
+        left_on="ts",
+        right_on=ts_merge,
+        allow_exact_matches=False,
+        direction="backward",
+    )
+    expected = pd.DataFrame(
+        {
+            "a": [2, 6],
+            "ts": [pd.Timestamp("2021/01/01 00:37"), pd.Timestamp("2021/01/01 01:40")],
+            "b": [4, 8],
+        }
+    )
+    tm.assert_frame_equal(result, expected)