diff --git a/doc/source/whatsnew/v2.0.0.rst b/doc/source/whatsnew/v2.0.0.rst
index d6e0bb2ae0830..316b4dd817b5a 100644
--- a/doc/source/whatsnew/v2.0.0.rst
+++ b/doc/source/whatsnew/v2.0.0.rst
@@ -83,6 +83,7 @@ Other enhancements
 - :func:`timedelta_range` now supports a ``unit`` keyword ("s", "ms", "us", or "ns") to specify the desired resolution of the output index (:issue:`49824`)
 - :meth:`DataFrame.to_json` now supports a ``mode`` keyword with supported inputs 'w' and 'a'. Defaulting to 'w', 'a' can be used when lines=True and orient='records' to append record oriented json lines to an existing json file. (:issue:`35849`)
 - Added ``name`` parameter to :meth:`IntervalIndex.from_breaks`, :meth:`IntervalIndex.from_arrays` and :meth:`IntervalIndex.from_tuples` (:issue:`48911`)
+- Improved error message for :func:`merge_asof` when join-columns were duplicated (:issue:`50102`)
 - Added :meth:`Index.infer_objects` analogous to :meth:`Series.infer_objects` (:issue:`50034`)
 - Added ``copy`` parameter to :meth:`Series.infer_objects` and :meth:`DataFrame.infer_objects`, passing ``False`` will avoid making copies for series or columns that are already non-object or where no better dtype can be inferred (:issue:`50096`)
 - :meth:`DataFrame.plot.hist` now recognizes ``xlabel`` and ``ylabel`` arguments (:issue:`49793`)
diff --git a/pandas/core/reshape/merge.py b/pandas/core/reshape/merge.py
index 16f1a5d0b81e2..8466db5a9e83f 100644
--- a/pandas/core/reshape/merge.py
+++ b/pandas/core/reshape/merge.py
@@ -1933,7 +1933,7 @@ def _validate_left_right_on(self, left_on, right_on):
                 lo_dtype = left_on_0.dtype
             else:
                 lo_dtype = (
-                    self.left[left_on_0].dtype
+                    self.left._get_label_or_level_values(left_on_0).dtype
                     if left_on_0 in self.left.columns
                     else self.left.index.get_level_values(left_on_0)
                 )
@@ -1946,7 +1946,7 @@ def _validate_left_right_on(self, left_on, right_on):
                 ro_dtype = right_on_0.dtype
             else:
                 ro_dtype = (
-                    self.right[right_on_0].dtype
+                    self.right._get_label_or_level_values(right_on_0).dtype
                     if right_on_0 in self.right.columns
                     else self.right.index.get_level_values(right_on_0)
                 )
diff --git a/pandas/tests/reshape/merge/test_merge_asof.py b/pandas/tests/reshape/merge/test_merge_asof.py
index 4d9c200fcaed6..4123f686163d4 100644
--- a/pandas/tests/reshape/merge/test_merge_asof.py
+++ b/pandas/tests/reshape/merge/test_merge_asof.py
@@ -1567,3 +1567,18 @@ def test_merge_asof_array_as_on():
         }
     )
     tm.assert_frame_equal(result, expected)
+
+
+def test_merge_asof_raise_for_duplicate_columns():
+    # GH#50102
+    left = pd.DataFrame([[1, 2, "a"]], columns=["a", "a", "left_val"])
+    right = pd.DataFrame([[1, 1, 1]], columns=["a", "a", "right_val"])
+
+    with pytest.raises(ValueError, match="column label 'a'"):
+        merge_asof(left, right, on="a")
+
+    with pytest.raises(ValueError, match="column label 'a'"):
+        merge_asof(left, right, left_on="a", right_on="right_val")
+
+    with pytest.raises(ValueError, match="column label 'a'"):
+        merge_asof(left, right, left_on="left_val", right_on="a")