Ralph Hasenhuttl revealed defender Jack Stephens is facing around three months on the sidelines with the knee injury he suffered at the weekend after Southampton beat Sheffield United on penalties on Tuesday.
The 27-year-old, who has had knee issues in the past, was forced off just before half-time during the goalless draw with Manchester City on Saturday after dropping to the floor and clutching his right leg.
Saints have had time to assess the damage and scans have revealed a tendon problem that will keep Stephens out for a lengthy spell.
Following his side's Carabao Cup win on Tuesday night, Southampton boss Hasenhuttl said: "His tendon on the knee is disrupted. I don't know how long, it could be 10 to 12 weeks, but it will take quite a serious time."
Fraser Forster was Saints' penalty hero at Bramall Lane as they edged past the Sky Bet Championship team to reach the fourth round.
Enda Stevens marked his return from injury and first appearance of the season with the opening goal after eight minutes but strikes from Ibrahima Diallo and Mohammed Salisu turned the game on its head.
Foderingham also saved a penalty from Armando Broja in the shoot-out but it was not enough for the hosts, with Brewster and McBurnie missing either side of the on-loan Chelsea youngster's kick.
Hasenhuttl added: "It was a typical cup-tie. It was not easy, it was a team who was in the Premier League last season and who still have Premier League players.
"I think they did a good job. They had a lot of pressure and were very aggressive. There was no difference between the teams. Sometimes you see the difference in the different leagues, but not here.
"It was not so easy against a team in the Championship, you have to work hard and find your way into the game. Both teams could have won it in the 90 minutes, but Fraser Forster was good for us in the shoot-out. We are in the next round and I am very happy."
Blades boss Slavisa Jokanovic thought his team acquitted themselves well and felt there were plenty of positives to take from the match, despite going out of the competition.
"I am satisfied as my team showed a great attitude. We played a decent game against a complicated opponent for us," said Jokanovic.
"This was the right way for my team to fight and even though we are out, it is positive. I am very proud, unfortunately the lottery of penalties has done us.
"There is still a big gap and we still need to improve but it is another step in the right direction."
On the penalties, Jokanovic said: "We always finish the training session with penalties before a cup match, it is not about leaving it to chance.
"It wasn't easy as the size of the keeper is huge and he made very good saves, it is not that the penalties were especially bad."