As the manager had revealed in his pre-match press conference, Chris Richards misses the trip to the South Coast with a calf injury.
The defender is replaced in the side by Nathaniel Clyne, who made 104 appearances across three seasons with the Saints between 2012 and 2015.
Otherwise, Palace are unchanged from the side which saw off Fulham 3-0 at Craven Cottage on Saturday to advance to the FA Cup semi-finals.
On the bench, Joel Ward – having recovered from long-term injury – makes his first appearance in a matchday squad since late August, with Matheus França also making his second appearance in a Premier League matchday squad this season.
Southampton boss Ivan Juric makes four changes to the Southampton side that suffered a 2-1 home defeat to Wolves before the international break.
Arnel Bella-Kotchap, Joe Aribo, Yukinari Sugawara and Tyler Dibling drop to the bench, with Jan Bednarek, Jack Stephens, Paul Onuachu and Flynn Downes coming in.
Palace: Henderson (GK), Clyne, Lacroix, Guéhi, Muñoz, Lerma, Wharton, Mitchell, Sarr, Mateta, Eze.
Subs: Turner (GK), Ward, Chilwell, Kporha, Devenny, Kamada, Esse, França, Nketiah.
Southampton: Ramsdale (GK), Walker-Peters, Downes, Bednarek, Harwood-Bellis, Manning, Stephens, Fernandes, Sulemana, Ugochukwu, Onuachu.
Subs: McCarthy (GK), Aribo, Bree, Wood, Sugawara, Archer, Dibling, Welington, Bella-Kotchap.
