Manager Roy Hodgson has limited options when it comes to rotation despite such a quick turnaround, and sticks with the same XI which got the 2-2 draw at the Etihad.
Six senior players are still missing for the Eagles, with suspended captain Luka Milivojevic among them.
Max Meyer has returned from his injury to offer Hodgson some small relief, though after such an impressive performance from his team-mates at the Etihad, the German only makes the bench.
Fresh from his debut goal, Cenk Tosun leads the line once more.
With Palace out of the FA Cup, come Wednesday morning Hodgson will have a 10-day break to help get those nearing a return back to full fitness.
Crystal Palace: Guaita, Kelly, Tomkins, Cahill, Riedewald, Ayew, Kouyate, McArthur, McCarthy, Zaha, Tosun
Subs: Ward, Dann, Meyer, Hennessey, Wickham, McGregor, Pierrick
Southampton: McCarthy, Cedric, Stephens, Vestergaard, Bertrand, Armstrong, Ward-Prowse, Hojbjerg, Redmond, Long, Obafemi
Subs: Yoshida, Ings, Adams, Djenepo, Romeu, Boufal, Gunn
Referee: Andre Marriner