Saints must tackle Aston Villa without the services of midfield pair Will Smallbone and Adam Lallana - plus long-term absentees Gavin Bazunu and Ross Stewart - while first-choice goalkeeper Aaron Ramsdale is still sidelined by a hand injury.
Furthermore, Jack Stephens was sent off during the first half of Wednesday's 5-1 defeat to Chelsea, so the experienced centre-back must now serve a suspension.
Fortunately, his replacement seems ready-made, as England defender Taylor Harwood-Bellis joins Flynn Downes and rising star Tyler Dibling in returning to the squad after one-match bans for yellow card accumulation.
Paul Onuachu and Jan Bednarek are expected to recover from recent injuries, though there are doubts whether either would be fit to start; Chelsea loanee Lesley Ugochukwu is also available again, having been blocked from playing against his parent club.
Meanwhile, Joe Lumley should feature between the posts again, after Ramsdale's deputy Alex McCarthy was dropped last week, starting behind what could effectively be a back five.
With Russell Martin set to make several changes, Adam Armstrong could be squeezed out of the lineup: since scoring in his first Premier League away game for Southampton back in August 2021, the ex-Blackburn Rovers forward has gone 32 league appearances without scoring a goal on the road.
Former Villa striker Cameron Archer should spearhead Saints' attack, making his latest return to his boyhood club.
Southampton possible starting lineup: Lumley; Sugawara, Walker-Peters, Harwood-Bellis, Wood, Manning; Dibling, Aribo, Downes, Fernandes; Archer
Written by
Jonathan O'Shea