Charlie Austin sustained an injury to his right shoulder to compound a miserable outing for Southampton in the Europa League on Thursday.
The Saints needed either a win or a goalless draw to progress at the expense of opponents Hapoel Be'er Sheva at St Mary's, but a 1-1 draw saw the Israeli side claim second place in Group K and a spot in the last 32.
Austin has suffered with a series of shoulder problems throughout his career and manager Claude Puel could not put a timescale on the most recent problem after the striker had to be replaced late in the first half.
"He has an injury with his shoulder, and I don't know how long he will stay out, but for the moment he is injured," Puel said.
"It's a big disappointment tonight. It was a difficult game against a good opponent, who were always dangerous when they recovered the ball, but we had chances during the game.
"Just one mistake, one shot at the end - we lost the ball and it's a goal. It's very hard to accept this situation, and very hard of course for my players. It's a big disappointment for all the squad and the fans also.
"Tonight, all the words are difficult, but this is football.
"It's a big disappointment, because we gave it our all. It's very hard to be eliminated, but now it's important to have a good reaction from all the team."
Southampton are back in Premier League action on Sunday, when they host Middlesbrough.