diff --git a/doc/source/whatsnew/v1.3.0.rst b/doc/source/whatsnew/v1.3.0.rst
index ab00b749d5725..c419884ee6ce1 100644
--- a/doc/source/whatsnew/v1.3.0.rst
+++ b/doc/source/whatsnew/v1.3.0.rst
@@ -276,6 +276,7 @@ Indexing
 - Bug in :meth:`DataFrame.loc`, :meth:`Series.loc`, :meth:`DataFrame.__getitem__` and :meth:`Series.__getitem__` returning incorrect elements for non-monotonic :class:`DatetimeIndex` for string slices (:issue:`33146`)
 - Bug in :meth:`DataFrame.reindex` and :meth:`Series.reindex` with timezone aware indexes raising ``TypeError`` for ``method="ffill"`` and ``method="bfill"`` and specified ``tolerance`` (:issue:`38566`)
 - Bug in :meth:`DataFrame.__setitem__` raising ``ValueError`` with empty :class:`DataFrame` and specified columns for string indexer and non empty :class:`DataFrame` to set (:issue:`38831`)
+- Bug in :meth:`DataFrame.loc.__setitem__` raising ValueError when expanding unique column for :class:`DataFrame` with duplicate columns (:issue:`38521`)
 - Bug in :meth:`DataFrame.iloc.__setitem__` and :meth:`DataFrame.loc.__setitem__` with mixed dtypes when setting with a dictionary value (:issue:`38335`)
 - Bug in :meth:`DataFrame.loc` dropping levels of :class:`MultiIndex` when :class:`DataFrame` used as input has only one row (:issue:`10521`)
 - Bug in setting ``timedelta64`` values into numeric :class:`Series` failing to cast to object dtype (:issue:`39086`)
diff --git a/pandas/core/indexing.py b/pandas/core/indexing.py
index 90ba03b312e56..1402354c9b2ca 100644
--- a/pandas/core/indexing.py
+++ b/pandas/core/indexing.py
@@ -1850,10 +1850,11 @@ def _setitem_single_block(self, indexer, value, name: str):
                     for i, idx in enumerate(indexer)
                     if i != info_axis
                 )
-                and item_labels.is_unique
             ):
-                self.obj[item_labels[indexer[info_axis]]] = value
-                return
+                selected_item_labels = item_labels[indexer[info_axis]]
+                if len(item_labels.get_indexer_for([selected_item_labels])) == 1:
+                    self.obj[selected_item_labels] = value
+                    return
 
             indexer = maybe_convert_ix(*indexer)
         if (isinstance(value, ABCSeries) and name != "iloc") or isinstance(value, dict):
diff --git a/pandas/tests/frame/indexing/test_setitem.py b/pandas/tests/frame/indexing/test_setitem.py
index 295c8a27e6ddd..e249da57e33be 100644
--- a/pandas/tests/frame/indexing/test_setitem.py
+++ b/pandas/tests/frame/indexing/test_setitem.py
@@ -373,6 +373,15 @@ def test_setitem_string_column_numpy_dtype_raising(self):
         expected = DataFrame([[1, 2, 5], [3, 4, 6]], columns=[0, 1, "0 - Name"])
         tm.assert_frame_equal(df, expected)
 
+    def test_setitem_empty_df_duplicate_columns(self):
+        # GH#38521
+        df = DataFrame(columns=["a", "b", "b"], dtype="float64")
+        df.loc[:, "a"] = list(range(2))
+        expected = DataFrame(
+            [[0, np.nan, np.nan], [1, np.nan, np.nan]], columns=["a", "b", "b"]
+        )
+        tm.assert_frame_equal(df, expected)
+
 
 class TestDataFrameSetItemSlicing:
     def test_setitem_slice_position(self):