diff --git a/doc/source/whatsnew/v1.3.0.rst b/doc/source/whatsnew/v1.3.0.rst
index 41db72612a66b..c5ff5265f6798 100644
--- a/doc/source/whatsnew/v1.3.0.rst
+++ b/doc/source/whatsnew/v1.3.0.rst
@@ -128,6 +128,7 @@ Other enhancements
 - :meth:`.Rolling.sum`, :meth:`.Expanding.sum`, :meth:`.Rolling.mean`, :meth:`.Expanding.mean`, :meth:`.Rolling.median`, :meth:`.Expanding.median`, :meth:`.Rolling.max`, :meth:`.Expanding.max`, :meth:`.Rolling.min`, and :meth:`.Expanding.min` now support ``Numba`` execution with the ``engine`` keyword (:issue:`38895`)
 - :meth:`DataFrame.apply` can now accept NumPy unary operators as strings, e.g. ``df.apply("sqrt")``, which was already the case for :meth:`Series.apply` (:issue:`39116`)
 - :meth:`DataFrame.apply` can now accept non-callable DataFrame properties as strings, e.g. ``df.apply("size")``, which was already the case for :meth:`Series.apply` (:issue:`39116`)
+- Disallow :class:`DataFrame` indexer for ``iloc`` for :meth:`Series.__getitem__` and :meth:`DataFrame.__getitem__`, (:issue:`39004`)
 - :meth:`Series.apply` can now accept list-like or dictionary-like arguments that aren't lists or dictionaries, e.g. ``ser.apply(np.array(["sum", "mean"]))``, which was already the case for :meth:`DataFrame.apply` (:issue:`39140`)
 - :meth:`DataFrame.plot.scatter` can now accept a categorical column as the argument to ``c`` (:issue:`12380`, :issue:`31357`)
 - :meth:`.Styler.set_tooltips` allows on hover tooltips to be added to styled HTML dataframes (:issue:`35643`, :issue:`21266`, :issue:`39317`)
@@ -318,6 +319,7 @@ Deprecations
 - Deprecated comparison of :class:`Timestamp` object with ``datetime.date`` objects.  Instead of e.g. ``ts <= mydate`` use ``ts <= pd.Timestamp(mydate)`` or ``ts.date() <= mydate`` (:issue:`36131`)
 - Deprecated :attr:`Rolling.win_type` returning ``"freq"`` (:issue:`38963`)
 - Deprecated :attr:`Rolling.is_datetimelike` (:issue:`38963`)
+- Deprecated :class:`DataFrame` indexer for :meth:`Series.__setitem__` and :meth:`DataFrame.__setitem__` (:issue:`39004`)
 - Deprecated :meth:`core.window.ewm.ExponentialMovingWindow.vol` (:issue:`39220`)
 - Using ``.astype`` to convert between ``datetime64[ns]`` dtype and :class:`DatetimeTZDtype` is deprecated and will raise in a future version, use ``obj.tz_localize`` or ``obj.dt.tz_localize`` instead (:issue:`38622`)
 - Deprecated casting ``datetime.date`` objects to ``datetime64`` when used as ``fill_value`` in :meth:`DataFrame.unstack`, :meth:`DataFrame.shift`, :meth:`Series.shift`, and :meth:`DataFrame.reindex`, pass ``pd.Timestamp(dateobj)`` instead (:issue:`39767`)
diff --git a/pandas/core/indexing.py b/pandas/core/indexing.py
index cfe16627d5c64..e322cb23eba95 100644
--- a/pandas/core/indexing.py
+++ b/pandas/core/indexing.py
@@ -1421,6 +1421,15 @@ def _has_valid_setitem_indexer(self, indexer) -> bool:
         if isinstance(indexer, dict):
             raise IndexError("iloc cannot enlarge its target object")
 
+        if isinstance(indexer, ABCDataFrame):
+            warnings.warn(
+                "DataFrame indexer for .iloc is deprecated and will be removed in"
+                "a future version.\n"
+                "consider using .loc with a DataFrame indexer for automatic alignment.",
+                FutureWarning,
+                stacklevel=3,
+            )
+
         if not isinstance(indexer, tuple):
             indexer = _tuplify(self.ndim, indexer)
 
@@ -1508,6 +1517,12 @@ def _get_list_axis(self, key, axis: int):
             raise IndexError("positional indexers are out-of-bounds") from err
 
     def _getitem_axis(self, key, axis: int):
+        if isinstance(key, ABCDataFrame):
+            raise IndexError(
+                "DataFrame indexer is not allowed for .iloc\n"
+                "Consider using .loc for automatic alignment."
+            )
+
         if isinstance(key, slice):
             return self._get_slice_axis(key, axis=axis)
 
diff --git a/pandas/tests/indexing/test_iloc.py b/pandas/tests/indexing/test_iloc.py
index 43ffc9e8eaedd..d0fdf81121c71 100644
--- a/pandas/tests/indexing/test_iloc.py
+++ b/pandas/tests/indexing/test_iloc.py
@@ -1090,6 +1090,20 @@ def test_iloc_getitem_setitem_fancy_exceptions(self, float_frame):
             # GH#32257 we let numpy do validation, get their exception
             float_frame.iloc[:, :, :] = 1
 
+    def test_iloc_frame_indexer(self):
+        # GH#39004
+        df = DataFrame({"a": [1, 2, 3]})
+        indexer = DataFrame({"a": [True, False, True]})
+        with tm.assert_produces_warning(FutureWarning):
+            df.iloc[indexer] = 1
+
+        msg = (
+            "DataFrame indexer is not allowed for .iloc\n"
+            "Consider using .loc for automatic alignment."
+        )
+        with pytest.raises(IndexError, match=msg):
+            df.iloc[indexer]
+
 
 class TestILocSetItemDuplicateColumns:
     def test_iloc_setitem_scalar_duplicate_columns(self):