Charlie Austin will be out for three-to-four weeks with a hamstring injury, while Shane Long will also miss Saturday's match against Sunderland, Ronald Koeman has confirmed.
Both Austin and Long were forced off during the second half of Tuesday night's 2-0 defeat at AFC Bournemouth and will now be unavailable for the visits of the Black Cats this weekend.
While Long seems likely to provide a boost by being back for the trip to Stoke City the following weekend, Saints will have to do without January signing Austin for a longer period.
"Charlie is out," Koeman told Southampton's official YouTube channel. "Of course, that was what we expected, because really at that time it was about a hamstring.
"It's grade one. That means that Charlie will be out three-to-four weeks. Ok, that's bad news, but we have to take it.
"Shane is much better, but is not available for the weekend. He had some problems with his knee, about a kick in the match against Bournemouth. He's not available for the weekend, but we have good hope after the weekend that he will be fit again to play."
Koeman added that there are no other fresh injury concerns following the midweek Cherries game.