Mikel Arteta has made five changes from Saturday with Nketiah, Martinelli, Pepe, Elneny, and Gabriel come out.
The five players have been replaced by Luiz, Smith Rowe, Partey, Saka, and Lacazette. Kieran Tierney doesn't make the squad, so Cedric keeps his place at left-back.
There will no doubt be a few raised eyebrows at Nicolas Pepe getting another start after an underwhelming performance here on Saturday, but fans will be encouraged to see Bukayo Saka and Emile Smith Rowe back in Arsenal's XI given their recent form.
The hosts make just the two forced changes from the 1-0 win over Arsenal at the weekend, with Valery and Vokins coming in at full-back to replace Walker-Peters and Bertrand.
Southampton XI: McCarthy, Valery, Stephens, Bednarek, Vokins, Armstrong Diallo, Ward-Prowse, Walcott, Adams, Ings
Subs: Forster, Long, Redmond, Ramsay, N'Lundulu, Ferry, Jankewitz, Watts, Chauke
Arsenal XI: Leno, Bellerin, Holding, Luiz, Cedric, Partey, Xhaka, Smith Rowe, Saka, Pepe, Lacazette
Subs: Ryan, Gabriel, Willian, Maitland-Niles, Chambers, Elneny, Willock, Nketiah, Martinelli
Follow Southampton vs Arsenal live on Futaa.
