diff --git a/doc/source/whatsnew/v3.0.0.rst b/doc/source/whatsnew/v3.0.0.rst
index 4ab20623cc561..375f788cb12b7 100644
--- a/doc/source/whatsnew/v3.0.0.rst
+++ b/doc/source/whatsnew/v3.0.0.rst
@@ -1150,6 +1150,7 @@ Indexing
 - Bug in :meth:`Series.__setitem__` when assigning boolean series with boolean indexer will raise ``LossySetitemError`` (:issue:`57338`)
 - Bug in printing :attr:`Index.names` and :attr:`MultiIndex.levels` would not escape single quotes (:issue:`60190`)
 - Bug in reindexing of :class:`DataFrame` with :class:`PeriodDtype` columns in case of consolidated block (:issue:`60980`, :issue:`60273`)
+- Bug in :meth:`DataFrame.__setitem__` throwing a ``ValueError`` when setting a column with a 2D object array (:issue:`61026`)
 - Bug in :meth:`DataFrame.loc.__getitem__` and :meth:`DataFrame.iloc.__getitem__` with a :class:`CategoricalDtype` column with integer categories raising when trying to index a row containing a ``NaN`` entry (:issue:`58954`)
 - Bug in :meth:`Index.__getitem__` incorrectly raising with a 0-dim ``np.ndarray`` key (:issue:`55601`)
 - Bug in :meth:`Index.get_indexer` not casting missing values correctly for new string datatype (:issue:`55833`)
diff --git a/pandas/core/frame.py b/pandas/core/frame.py
index c8c246434f6d8..273e70140538b 100644
--- a/pandas/core/frame.py
+++ b/pandas/core/frame.py
@@ -5502,7 +5502,30 @@ def _sanitize_column(self, value) -> tuple[ArrayLike, BlockValuesRefs | None]:
 
         if is_list_like(value):
             com.require_length_match(value, self.index)
-        return sanitize_array(value, self.index, copy=True, allow_2d=True), None
+
+        # GH#61026: special-case 2D inputs for single-column assignment.
+        # - accept shape (n, 1) by flattening to 1D
+        # - disallow 2D *object* arrays with more than one column, since those
+        # correspond to a single column key and should be rejected
+        arr = value
+
+        # np.matrix is always 2D; gonna convert to regular ndarray
+        if isinstance(arr, np.matrix):
+            arr = np.asarray(arr)
+
+        if isinstance(arr, np.ndarray) and arr.ndim == 2:
+            if arr.shape[1] == 1:
+                # treating (n, 1) as a length-n 1D array
+                arr = arr[:, 0]
+            elif arr.dtype == object:
+                # single-column setitem with a 2D object array is not allowed.
+                msg = (
+                    "Setting a DataFrame column with a 2D array requires "
+                    f"shape (n, 1); got shape {arr.shape}."
+                )
+                raise ValueError(msg)
+        subarr = sanitize_array(arr, self.index, copy=True, allow_2d=True)
+        return subarr, None
 
     @property
     def _series(self):
diff --git a/pandas/tests/frame/indexing/test_setitem.py b/pandas/tests/frame/indexing/test_setitem.py
index 0de2455079027..9d631026fc074 100644
--- a/pandas/tests/frame/indexing/test_setitem.py
+++ b/pandas/tests/frame/indexing/test_setitem.py
@@ -816,6 +816,24 @@ def test_setitem_index_object_dtype_not_inferring(self):
         )
         tm.assert_frame_equal(df, expected)
 
+    def test_setitem_2d_object_array(self):
+        # GH#61026
+        df = DataFrame(
+            {
+                "c1": [1, 2, 3, 4, 5],
+            }
+        )
+
+        arr = np.array([["A"], ["B"], ["C"], ["D"], ["E"]], dtype=object)
+        df["c1"] = arr
+
+        expected = DataFrame(
+            {
+                "c1": ["A", "B", "C", "D", "E"],
+            }
+        )
+        tm.assert_frame_equal(df, expected)
+
 
 class TestSetitemTZAwareValues:
     @pytest.fixture