The hosts are dealing with their own injury crisis at present, and visiting manager Ralph Hasenhuttl's hand will be forced in most areas of the pitch due to a number of absentees as well.
In goal, Fraser Forster was surprisingly given the nod over Alex McCarthy against Everton, and while Hasenhuttl has affirmed that he has not decided who will start at Bramall Lane, McCarthy will hope to earn a recall.
Kyle-Walker Peters has a chance of returning from his hamstring problem for the weekend, but Jan Bednarek should continue at right-back for now, while Jannik Vestergaard, Mohammed Salisu and Ryan Bertrand are all set to retain their places in defence.
Hasenhuttl could be without as many as three wingers for this game, as Moussa Djenepo's involvement is uncertain following a heavy tackle in the Goodison Park defeat, while Theo Walcott is definitely out and Takumi Minamino is a doubt.
Nathan Tella is ready to step in if required, but Hasenhuttl is optimistic that Minamino could feature and he will most likely be given the nod if available, while Nathan Redmond's spot on the right is safe.
Danny Ings has not scored away from home in the Premier League in 2021 and boasts just one goal from his last eight top-flight outings, but he will be hoping to rediscover his goalscoring touch alongside Che Adams against a ravaged Blades backline this weekend.
Southampton possible starting lineup:
McCarthy; Bednarek, Vestergaard, Salisu, Bertrand; Redmond, Armstrong, Ward-Prowse, Minamino; Ings, Adams
Watch the Sports Mole Football Shorts prediction for this game below: