diff --git a/doc/source/whatsnew/v2.1.0.rst b/doc/source/whatsnew/v2.1.0.rst
index 988d63db2229f..fa4f4b8cf4b45 100644
--- a/doc/source/whatsnew/v2.1.0.rst
+++ b/doc/source/whatsnew/v2.1.0.rst
@@ -283,6 +283,7 @@ Performance improvements
 - Performance improvement accessing :attr:`arrays.IntegerArrays.dtype` & :attr:`arrays.FloatingArray.dtype` (:issue:`52998`)
 - Performance improvement in :class:`Series` reductions (:issue:`52341`)
 - Performance improvement in :func:`concat` when ``axis=1`` and objects have different indexes (:issue:`52541`)
+- Performance improvement in :meth:`DataFrame.loc` when selecting rows and columns (:issue:`53014`)
 - Performance improvement in :meth:`Series.corr` and :meth:`Series.cov` for extension dtypes (:issue:`52502`)
 - Performance improvement in :meth:`Series.to_numpy` when dtype is a numpy float dtype and ``na_value`` is ``np.nan`` (:issue:`52430`)
 - Performance improvement in :meth:`~arrays.ArrowExtensionArray.to_numpy` (:issue:`52525`)
diff --git a/pandas/core/indexing.py b/pandas/core/indexing.py
index 0f1cd397f2dd1..2a3119515bb99 100644
--- a/pandas/core/indexing.py
+++ b/pandas/core/indexing.py
@@ -933,7 +933,9 @@ def _getitem_tuple_same_dim(self, tup: tuple):
         This is only called after a failed call to _getitem_lowerdim.
         """
         retval = self.obj
-        for i, key in enumerate(tup):
+        # Selecting columns before rows is signficiantly faster
+        for i, key in enumerate(reversed(tup)):
+            i = self.ndim - i - 1
             if com.is_null_slice(key):
                 continue