"I don't think it's good," Rams coach Sean McVay said after the game. "We'll get the MRI, but it doesn't look good right now."
Kupp suffered the injury in the fourth quarter, on a play away from the ball, when he was running a route, jostled a bit with the defender, then went to the ground and grabbed his knee. Kupp walked off the field with assistance from the training staff.
"He's been a valuable piece of our team and a guy we'll miss," Jared Goff said.
Kupp has dealt with a series of injuries this season.
He was placed into concussion protocol during halftime of a Week 5 victory at Seattle, but was cleared to play the following week in Denver.
But in the first half against the Denver Broncos, Kupp was tackled by the horse collar and sprained his knee as he awkwardly went to the ground. He tried to play a series in the second half of that matchup, but was ultimately sidelined for two weeks.
A second-year pro, Kupp has played a pivotal part in the offense this season. He has caught 35 passes for 527 yards and 6 touchdowns.