diff --git a/pandas/core/common.py b/pandas/core/common.py
index 2bf925466e176..f4dcbc20dc5fd 100644
--- a/pandas/core/common.py
+++ b/pandas/core/common.py
@@ -240,7 +240,8 @@ def asarray_tuplesafe(values, dtype: NpDtype | None = None) -> np.ndarray:
     if issubclass(result.dtype.type, str):
         result = np.asarray(values, dtype=object)
 
-    if result.ndim == 2:
+    # For ndim > 2 distinguish between nested tuples and multidimensional arrays
+    if result.ndim == 2 or (result.ndim > 2 and isinstance(values[0][0], tuple)):
         # Avoid building an array of arrays:
         values = [tuple(x) for x in values]
         result = construct_1d_object_array_from_listlike(values)
diff --git a/pandas/tests/frame/indexing/test_getitem.py b/pandas/tests/frame/indexing/test_getitem.py
index 3028a433f2dae..03c61b44058d9 100644
--- a/pandas/tests/frame/indexing/test_getitem.py
+++ b/pandas/tests/frame/indexing/test_getitem.py
@@ -160,6 +160,15 @@ def test_getitem_iloc_two_dimensional_generator(self):
         expected = Series([5, 6], name="b", index=[1, 2])
         tm.assert_series_equal(result, expected)
 
+    def test_getitem_key_nested_tuple(self):
+        # GH 43780
+        df = DataFrame([[0, 0]], columns=Index([(("a",), (1,)), (("b",), (2,))]))
+        key_list = [df.columns[0]]
+        result = df[key_list]
+
+        expected = DataFrame([0], columns=Index(key_list))
+        tm.assert_frame_equal(result, expected)
+
 
 class TestGetitemCallable:
     def test_getitem_callable(self, float_frame):