diff --git a/doc/source/whatsnew/v2.0.0.rst b/doc/source/whatsnew/v2.0.0.rst
index d6e0bb2ae0830..b41768a215b68 100644
--- a/doc/source/whatsnew/v2.0.0.rst
+++ b/doc/source/whatsnew/v2.0.0.rst
@@ -753,6 +753,7 @@ Indexing
 - Bug in :meth:`DataFrame.loc` raising ``ValueError`` with ``bool`` indexer and :class:`MultiIndex` (:issue:`47687`)
 - Bug in :meth:`DataFrame.__setitem__` raising ``ValueError`` when right hand side is :class:`DataFrame` with :class:`MultiIndex` columns (:issue:`49121`)
 - Bug in :meth:`DataFrame.reindex` casting dtype to ``object`` when :class:`DataFrame` has single extension array column when re-indexing ``columns`` and ``index`` (:issue:`48190`)
+- Bug in :meth:`DataFrame.iloc` raising ``IndexError`` when indexer is a :class:`Series` with numeric extension array dtype (:issue:`49521`)
 - Bug in :func:`~DataFrame.describe` when formatting percentiles in the resulting index showed more decimals than needed (:issue:`46362`)
 - Bug in :meth:`DataFrame.compare` does not recognize differences when comparing ``NA`` with value in nullable dtypes (:issue:`48939`)
 -
diff --git a/pandas/core/indexing.py b/pandas/core/indexing.py
index 070ec7c7a2e4a..9bcbedccba1e6 100644
--- a/pandas/core/indexing.py
+++ b/pandas/core/indexing.py
@@ -1481,7 +1481,12 @@ def _validate_key(self, key, axis: AxisInt):
             # so don't treat a tuple as a valid indexer
             raise IndexingError("Too many indexers")
         elif is_list_like_indexer(key):
-            arr = np.array(key)
+            if isinstance(key, ABCSeries):
+                arr = key._values
+            elif is_array_like(key):
+                arr = key
+            else:
+                arr = np.array(key)
             len_axis = len(self.obj._get_axis(axis))
 
             # check that the key has a numeric dtype
diff --git a/pandas/tests/frame/indexing/test_indexing.py b/pandas/tests/frame/indexing/test_indexing.py
index 81a5e3d9947be..5ce8800de1f67 100644
--- a/pandas/tests/frame/indexing/test_indexing.py
+++ b/pandas/tests/frame/indexing/test_indexing.py
@@ -1437,6 +1437,28 @@ def test_loc_rhs_empty_warning(self):
             df.loc[:, "a"] = rhs
         tm.assert_frame_equal(df, expected)
 
+    def test_iloc_ea_series_indexer(self):
+        # GH#49521
+        df = DataFrame([[0, 1, 2, 3, 4], [5, 6, 7, 8, 9]])
+        indexer = Series([0, 1], dtype="Int64")
+        row_indexer = Series([1], dtype="Int64")
+        result = df.iloc[row_indexer, indexer]
+        expected = DataFrame([[5, 6]], index=[1])
+        tm.assert_frame_equal(result, expected)
+
+        result = df.iloc[row_indexer.values, indexer.values]
+        tm.assert_frame_equal(result, expected)
+
+    def test_iloc_ea_series_indexer_with_na(self):
+        # GH#49521
+        df = DataFrame([[0, 1, 2, 3, 4], [5, 6, 7, 8, 9]])
+        indexer = Series([0, pd.NA], dtype="Int64")
+        msg = "cannot convert"
+        with pytest.raises(ValueError, match=msg):
+            df.iloc[:, indexer]
+        with pytest.raises(ValueError, match=msg):
+            df.iloc[:, indexer.values]
+
     @pytest.mark.parametrize("indexer", [True, (True,)])
     @pytest.mark.parametrize("dtype", [bool, "boolean"])
     def test_loc_bool_multiindex(self, dtype, indexer):