diff --git a/doc/source/user_guide/indexing.rst b/doc/source/user_guide/indexing.rst
index 77eee8e58a5e8..e514d3c320265 100644
--- a/doc/source/user_guide/indexing.rst
+++ b/doc/source/user_guide/indexing.rst
@@ -62,6 +62,8 @@ of multi-axis indexing.
     * A boolean array (any ``NA`` values will be treated as ``False``).
     * A ``callable`` function with one argument (the calling Series or DataFrame) and
       that returns valid output for indexing (one of the above).
+    * A tuple of row (and column) indices whose elements are one of the
+      above inputs.
 
   See more at :ref:`Selection by Label <indexing.label>`.
 
@@ -78,6 +80,8 @@ of multi-axis indexing.
     * A boolean array (any ``NA`` values will be treated as ``False``).
     * A ``callable`` function with one argument (the calling Series or DataFrame) and
       that returns valid output for indexing (one of the above).
+    * A tuple of row (and column) indices whose elements are one of the
+      above inputs.
 
   See more at :ref:`Selection by Position <indexing.integer>`,
   :ref:`Advanced Indexing <advanced>` and :ref:`Advanced
@@ -85,6 +89,12 @@ of multi-axis indexing.
 
 * ``.loc``, ``.iloc``, and also ``[]`` indexing can accept a ``callable`` as indexer. See more at :ref:`Selection By Callable <indexing.callable>`.
 
+  .. note::
+
+     Destructuring tuple keys into row (and column) indexes occurs
+     *before* callables are applied, so you cannot return a tuple from
+     a callable to index both rows and columns.
+
 Getting values from an object with multi-axes selection uses the following
 notation (using ``.loc`` as an example, but the following applies to ``.iloc`` as
 well). Any of the axes accessors may be the null slice ``:``. Axes left out of
@@ -446,6 +456,8 @@ The ``.iloc`` attribute is the primary access method. The following are valid in
 * A slice object with ints ``1:7``.
 * A boolean array.
 * A ``callable``, see :ref:`Selection By Callable <indexing.callable>`.
+* A tuple of row (and column) indexes, whose elements are one of the
+  above types.
 
 .. ipython:: python
 
@@ -547,6 +559,12 @@ Selection by callable
 ``.loc``, ``.iloc``, and also ``[]`` indexing can accept a ``callable`` as indexer.
 The ``callable`` must be a function with one argument (the calling Series or DataFrame) that returns valid output for indexing.
 
+.. note::
+
+   For ``.iloc`` indexing, returning a tuple from the callable is
+   not supported, since tuple destructuring for row and column indexes
+   occurs *before* applying callables.
+
 .. ipython:: python
 
    df1 = pd.DataFrame(np.random.randn(6, 4),
diff --git a/doc/source/whatsnew/v2.1.0.rst b/doc/source/whatsnew/v2.1.0.rst
index 44691e4265f5b..69f214ea96d03 100644
--- a/doc/source/whatsnew/v2.1.0.rst
+++ b/doc/source/whatsnew/v2.1.0.rst
@@ -298,6 +298,7 @@ Deprecations
 - Deprecated parameter ``obj`` in :meth:`GroupBy.get_group` (:issue:`53545`)
 - Deprecated positional indexing on :class:`Series` with :meth:`Series.__getitem__` and :meth:`Series.__setitem__`, in a future version ``ser[item]`` will *always* interpret ``item`` as a label, not a position (:issue:`50617`)
 - Deprecated strings ``T``, ``t``, ``L`` and ``l`` denoting units in :func:`to_timedelta` (:issue:`52536`)
+- Deprecated support for returning a tuple from a callable in ``iloc``-indexing. Place callables inside a tuple if you need to generate row and column indices using functions (:issue:`53533`)
 - Deprecated the "method" and "limit" keywords on :meth:`Series.fillna`, :meth:`DataFrame.fillna`, :meth:`SeriesGroupBy.fillna`, :meth:`DataFrameGroupBy.fillna`, and :meth:`Resampler.fillna`, use ``obj.bfill()`` or ``obj.ffill()`` instead (:issue:`53394`)
 - Deprecated the ``method`` and ``limit`` keywords in :meth:`DataFrame.replace` and :meth:`Series.replace` (:issue:`33302`)
 - Deprecated values "pad", "ffill", "bfill", "backfill" for :meth:`Series.interpolate` and :meth:`DataFrame.interpolate`, use ``obj.ffill()`` or ``obj.bfill()`` instead (:issue:`53581`)
diff --git a/pandas/core/indexing.py b/pandas/core/indexing.py
index 381f9c6ab0897..5666c932c712b 100644
--- a/pandas/core/indexing.py
+++ b/pandas/core/indexing.py
@@ -163,7 +163,8 @@ def iloc(self) -> _iLocIndexer:
         - A ``callable`` function with one argument (the calling Series or
           DataFrame) and that returns valid output for indexing (one of the above).
           This is useful in method chains, when you don't have a reference to the
-          calling object, but would like to base your selection on some value.
+          calling object, but would like to base your selection on
+          some value. Note that returning a tuple from a callable is deprecated.
         - A tuple of row and column indexes. The tuple elements consist of one of the
           above inputs, e.g. ``(0, 1)``.
 
diff --git a/pandas/tests/frame/indexing/test_indexing.py b/pandas/tests/frame/indexing/test_indexing.py
index 9005798d66d17..159c7ec18a2b0 100644
--- a/pandas/tests/frame/indexing/test_indexing.py
+++ b/pandas/tests/frame/indexing/test_indexing.py
@@ -1000,6 +1000,14 @@ def test_single_element_ix_dont_upcast(self, float_frame):
         result = df.loc[[0], "b"]
         tm.assert_series_equal(result, expected)
 
+    def test_iloc_callable_tuple_return_value(self):
+        df = DataFrame(np.random.randn(10, 4), index=range(0, 20, 2))
+        msg = "callable in iLocation indexing is deprecated"
+        with tm.assert_produces_warning(FutureWarning, match=msg):
+            df.iloc[lambda _: (0,)]
+        with tm.assert_produces_warning(FutureWarning, match=msg):
+            df.iloc[lambda _: (0,)] = 1
+
     def test_iloc_row(self):
         df = DataFrame(np.random.randn(10, 4), index=range(0, 20, 2))