Rashford has suffered a double stress fracture in his back and faces at least six weeks out, Manchester United manager Ole Gunnar Solskjaer confirmed.
England international Rashford hobbled out of the midweek FA Cup win against Wolves, having come on as a substitute.
Solskjaer revealed after the match his striker had already been dealing with a back problem, although he was initially hopeful Rashford would play against Liverpool on Sunday.
Rashford missed the 2-0 defeat and is now facing a lengthy spell on the sidelines, dealing a blow to both fifth-placed United, as their topscorer, and England ahead of Euro 2020.
“He’s suffered a bad injury,” Solskjaer told Sky Sports after the loss at Anfield.
“It’s a stress fracture that happened against Wolverhampton, and it’s not something that has happened before. It was there and then.
“It’s unlucky for Marcus. He’ll be out for a while for us. He won’t be back until after the mid-season break [in mid-February].
“I don’t know how long it is, I’m not a doctor, but normally a stress fracture is six weeks to heal and then he needs some rehab after that probably.”
Solskjaer acknowledged United may now have to consider a loan move to bring in cover for Rashford, who has 14 Premier League goals to his name.
“We’ve had many, many injuries for big players for us this season,” he said.
“Now Marcus, Anthony [Martial] has been out for months, Paul [Pogba] has been out for more than half the season, Scott [McTominay] has been out for months. It’s just an unfortunate situation we’re in.
“Because the window is open, we might look at some short-term deals as well. That could take us through until the summer.
“Desperately [need a signing]? Not desperately. Of course, we’re looking at numbers as well. We’ve had many injuries.
“If the right one’s there and it fits for us, we can buy. If there’s loans available, it might be possible. But I’ve got players here as well who are chomping at the bit.”