Harry Maguire has been ruled out for several weeks with a calf injury, Ole Gunnar Solskjaer has revealed.
The Manchester United skipper suffered the injury in Saturday's 1-0 home defeat to Aston Villa and is set to miss a key run of games - including Wednesday's Champions League tie with Villarreal.
Solskjaer said: "Harry is, more or less, definitely out and it doesn't look good. It's Harry's calf and it might take a few weeks. Let's see how quickly he recovers.
"Of course, he was hoping to play against Villarreal before but he missed the last game we played against them. That's football for you.
"With Aaron [Wan-Bissaka] suspended, we will have to make a few changes."
Luke Shaw also came off injured on Saturday, but Solskjaer said the left-back has an outside chance of being fit to face Villarreal, who beat United in last season's Europa League final.
"Luke, we might give a chance to, but he didn't train this morning," said Solskjaer. "So maybe the best case scenario is he will join us on the bench.
"There has to be a reshuffle, but that's why we have a big squad of good players and I'm sure we'll get a good performance with whoever is selected.
"Luke has been in today so I'll give him a chance to be involved. He didn't train with the team."
Saturday's clash against Villa was one to forget for the Old Trafford faithful, with two of their first choice back-four lasting less than 60 minutes before having to be replaced.
Maguire's commanding presence at the heart of United's defence will be sorely missed as they aim to bounce back from both defeat at the weekend and defeat in their first group stage fixture.
Solskjaer's side were on the wrong end of a shock 2-1 defeat on Champions League matchday one to Swiss outfit BSC Young Boys, Jesse Lingard's under-hit back-pass proving costly late on.
United have lost three of their last four games, but Solskjaer is determined to prove his team can achieve the level of consistency required to enjoy a successful season.
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"My focus is always to win the next game, short-term and think long-term about the squad building. My focus now has been on winning this game, getting back on track.
"Then we focus on the league again from Thursday morning. We would have loved to be top of the league, but we are still up there.
"With the squad and coaches I have got we can improve and we will get that consistency."
