Kupp suffered the injury in the fourth quarter on a play away from the ball. 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.
"It's a huge loss for our football team, he's such an important part of what we do and a great football player, a great person, and it's tough, but fortunately we've got guys that are ready to step up," McVay said.
Robert Woods is expected to play a larger role in the slot and Josh Reynolds is expected to return to the starting lineup. He started in place of Kupp when he was sidelined because of the earlier knee sprain.
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 he was cleared to play the following week in Denver.
But in the first half against the Denver Broncos, Kupp was brought down on a horse-collar tackle by safety Darian Stewart 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 he was ultimately sidelined for two weeks.
A second-year pro, Kupp has played a pivotal part in the offense this season. He has caught 40 passes for 566 yards and 6 touchdowns.