"It doesn't look good," St. Louis coach Steve Spagnuolo told reporters. "We'll know more tomorrow, but they said it had something to do with the patella (tendon). We're not optimistic."
Clayton had established himself as rookie quarterback Sam Bradford's favorite target and losing him, too, would be a significant setback for an offensive unit already lacking in playmakers.
"Everyone has seen what he's done for this offense in the first four games, and it is going to be tough to replace him," Bradford told reporters. "We just need someone to step up."
With Clayton out, Danny Amendola stepped up and had a career day. He caught 12 passes for 95 yards, but he also lost a costly fumble in the red zone that stalled a promising drive in the first quarter when the Rams trailed 3-0.
Rams running back Steven Jackson rushed for 114 yards on 25 carries, his first 100-yard rushing game of the season and the 24th of his career.
A week after having arguably his best game of the season, Bradford may have had his worst performance on Sunday. He completed 23 of 45 passes for 215 yards and was intercepted twice in the fourth quarter, with one by defensive tackle Ndamukong Suh and the other being returned by Alphonso Smith for a touchdown and the 44-6 final margin.
"There are going to be a lot of things that we have to find on the film and fix because we have to make sure this never happens again," Bradford said. "I don't think I've ever been part of a loss like this."
The win snapped a 10-game losing streak for the Lions and was their largest margin of victory in 15 years. It also avenged a home loss to the Rams last season, which was the only win for St. Louis in 2009.
The Rams were feeling good after rebounding from an 0-2 start to defeat the Washington Redskins — which snapped a 10-game losing streak for St. Louis — and the Seattle Seahawks the last two weeks at the Edward Jones Dome.
They will return to the Dome to host the San Diego Chargers (2-3), which lost to the Raiders 35-27 on Sunday, next weekend. But after Sunday's loss in Detroit, the Rams will return to St. Louis as a wounded group with plenty of questions about what kind of team they are.
Whatever momentum St. Louis gained with those two wins is now gone.