diff --git a/pandas/core/common.py b/pandas/core/common.py
index 2bf925466e176..21c66e9638cc8 100644
--- a/pandas/core/common.py
+++ b/pandas/core/common.py
@@ -248,7 +248,9 @@ def asarray_tuplesafe(values, dtype: NpDtype | None = None) -> np.ndarray:
     return result
 
 
-def index_labels_to_array(labels, dtype: NpDtype | None = None) -> np.ndarray:
+def index_labels_to_array(
+    labels, dtype: NpDtype | None = None, ndim: int | None = None
+) -> np.ndarray:
     """
     Transform label or iterable of labels to array, for use in Index.
 
@@ -261,9 +263,15 @@ def index_labels_to_array(labels, dtype: NpDtype | None = None) -> np.ndarray:
     -------
     array
     """
-    if isinstance(labels, (str, tuple)):
+    if isinstance(labels, str):
         labels = [labels]
 
+    if isinstance(labels, tuple):
+        if ndim == 1:
+            labels = list(labels)
+        else:
+            labels = [labels]
+
     if not isinstance(labels, (list, np.ndarray)):
         try:
             labels = list(labels)
diff --git a/pandas/core/indexes/base.py b/pandas/core/indexes/base.py
index 0cfd0e970a44c..09ed1bd4c8953 100644
--- a/pandas/core/indexes/base.py
+++ b/pandas/core/indexes/base.py
@@ -6448,7 +6448,7 @@ def drop(self, labels, errors: str_t = "raise") -> Index:
         if not isinstance(labels, Index):
             # avoid materializing e.g. RangeIndex
             arr_dtype = "object" if self.dtype == "object" else None
-            labels = com.index_labels_to_array(labels, dtype=arr_dtype)
+            labels = com.index_labels_to_array(labels, dtype=arr_dtype, ndim=self.ndim)
 
         indexer = self.get_indexer_for(labels)
         mask = indexer == -1
diff --git a/pandas/tests/frame/methods/test_drop.py b/pandas/tests/frame/methods/test_drop.py
index 1e2ce38a2fefd..9050e165e9365 100644
--- a/pandas/tests/frame/methods/test_drop.py
+++ b/pandas/tests/frame/methods/test_drop.py
@@ -546,3 +546,17 @@ def test_drop_level_missing_label_multiindex(self):
         df = DataFrame(index=MultiIndex.from_product([range(3), range(3)]))
         with pytest.raises(KeyError, match="labels \\[5\\] not found in level"):
             df.drop(5, level=0)
+
+    def test_drop_labels_is_tuple(self):
+        # GH 43978
+        df = DataFrame(np.arange(12).reshape(3, 4), columns=["A", "B", "C", "D"])
+        result = df.drop(columns=("A", "B"))
+        expected = DataFrame({"C": [2, 6, 10], "D": [3, 7, 11]})
+        tm.assert_frame_equal(result, expected)
+
+    def test_drop_columns_are_tuple(self):
+        # GH 43978
+        df = DataFrame(np.arange(6).reshape(3, 2), columns=[("A", "B"), ("C", "D")])
+        result = df.drop(columns=("A", "B"))
+        expected = DataFrame([1, 3, 5], columns=[("C", "D")])
+        tm.assert_frame_equal(result, expected)