Michael Carrick has confirmed that Riley McGree and Marcus Forss will miss the remainder of the season.
McGree picked up an injury on international duty last week and Forss was withdrawn late on in the game against Blackburn before the international break.
"Riley needs an operation and is out for the season, Marcus is out for the season too, which is desperately unfortunate," said the boss.
"It's a big blow for both of them. They've both had a big impact since I've been here when they've been available.
"Paddy McNair will be a few weeks as well. He did his hamstring in the 90th minute for Northern Ireland in midweek. It's another one to add to the list."
Boro were without 11 players at Southampton on Friday, including six defenders. Matt Clarke was the only fit senior centre-back available. Goalkeeper Tom Glover also missed out through illness.
"It's been incredible this season," added Carrick. "I know a lot of teams have had injuries and I understand that but it's been a revolving door. It's not the fault of the players at all and it's been crazy.
"We haven't been able to get a consistent team but the boys have adapted unbelievably well and keep finding a way.
"When you go through that it shows what you're all about."