diff --git a/doc/source/whatsnew/v3.0.0.rst b/doc/source/whatsnew/v3.0.0.rst
index 950082f9281c5..6313cdee1fd48 100644
--- a/doc/source/whatsnew/v3.0.0.rst
+++ b/doc/source/whatsnew/v3.0.0.rst
@@ -157,7 +157,7 @@ Strings
 
 Interval
 ^^^^^^^^
--
+- Bug in :meth:`DataFrame.iloc` raising error when indexing with a ``NamedTuple`` (:issue:`48188`)
 -
 
 Indexing
diff --git a/pandas/core/indexing.py b/pandas/core/indexing.py
index 2e7a237406ca5..8185dd0ea9ce9 100644
--- a/pandas/core/indexing.py
+++ b/pandas/core/indexing.py
@@ -1177,7 +1177,11 @@ def _check_deprecated_callable_usage(self, key: Any, maybe_callable: T) -> T:
     @final
     def __getitem__(self, key):
         check_dict_or_set_indexers(key)
-        if type(key) is tuple:
+        if (
+            type(key) is tuple
+            or isinstance(key, tuple)
+            and isinstance(self, _iLocIndexer)
+        ):
             key = tuple(list(x) if is_iterator(x) else x for x in key)
             key = tuple(com.apply_if_callable(x, self.obj) for x in key)
             if self._is_scalar_access(key):
diff --git a/pandas/tests/frame/indexing/test_indexing.py b/pandas/tests/frame/indexing/test_indexing.py
index 0373c15d15272..05348aaaa80df 100644
--- a/pandas/tests/frame/indexing/test_indexing.py
+++ b/pandas/tests/frame/indexing/test_indexing.py
@@ -1473,6 +1473,17 @@ def test_loc_named_tuple_for_midx(self):
         )
         tm.assert_frame_equal(result, expected)
 
+    def test_iloc_tuple_subclass(self, float_frame):
+        # GH#48188
+        indexer_tuple = namedtuple("Indexer", ["row", "col"])
+        idx = indexer_tuple(row=1, col=2)
+        assert float_frame.iloc[idx] == float_frame.iloc[1, 2]
+
+        idx = indexer_tuple(row=[1, 2], col=[1, 2])
+        result = float_frame.iloc[idx]
+        expected = float_frame.iloc[[1, 2], [1, 2]]
+        tm.assert_frame_equal(result, expected)
+
     @pytest.mark.parametrize("indexer", [["a"], "a"])
     @pytest.mark.parametrize("col", [{}, {"b": 1}])
     def test_set_2d_casting_date_to_int(self, col, indexer):