Milner is suspended after his dismissal against Crystal Palace last time out in the league, while Henderson was subbed at Old Trafford due to illness – he makes the bench though.
That means a rare league start for Joe Allen – his first since the draw against Sunderland at the start of February.
Also missing is Roberto Firmino, who picked up a hamstring injury in training which means he’s been withdrawn from the Brazil squad.
Alberto Moreno is also sidelined, while Martin Skrtel is back among the subs.
Kick off is 1.30pm GMT – it’s not live on TV in the UK. We’ll have live coverage from 1pm here on This Is Anfield.
— Jack Lusby (@jacklusby_) March 20, 2016
Liverpool: Mignolet, Flanagan, Lovren, Sakho, Clyne, Can, Allen, Lallana, Coutinho, Origi, Sturridge.
Subs: Ward, Toure, Benteke, Henderson, Skrtel, Smith, Ojo.
Southampton: Forster; Martina, Van Dijk, Fonte, Bertrand; Clasie, Romeu; Tadi?, Long, Davis; Pellè.
Subs: Stekelenburg, Cedric, Yoshida, Mane, Wanyama, Ward-Prowse, Juanmi.