Coach Steve Spagnuolo said Monday that Clayton will have season-ending surgery on his right knee to repair a torn patellar tendon. Clayton was hurt early in Sunday's 44-6 loss at Detroit.
"He's got a torn patella," Spagnuolo said. "So that's unfortunate for us."
"We certainly don't feel good about losing Mark because he's made a lot of plays for us, but we have to find a way to overcome that somehow," Spagnuolo said.
Clayton, acquired in a trade with Baltimore on Sept. 6, caught 22 passes for 300 yards and two touchdowns in the first four games. The 28-year-old Clayton, who was targeted 15 times in the Week 4 win over the Seattle Seahawks, was the Rams' leading receiver in each of those categories.
In Clayton's six seasons, including five with Baltimore, the former first-round pick had 257 receptions and 14 touchdowns in 81 career games. He had clearly established a good rapport with Bradford, the No. 1 overall pick and a rising star for the struggling franchise.
St. Louis (2-3) hosts San Diego (2-3) this weekend.
With Clayton out, the St. Louis receiving corps is reduced to four players on the active roster -- Danny Amendola, Laurent Robinson, Brandon Gibson and rookie Mardy Gilyard -- with a combined 183 receptions and six touchdowns in 64 career NFL games.
Spagnuolo mentioned practice squad wide receiver Danario Alexander, an undrafted rookie from Missouri, as a possibility to fill Clayton's roster spot.
Alexander, who had 113 receptions for 1,781 yards and 14 touchdowns during his senior season in 2009 at Missouri, is working his way back after knee surgery in the spring.
"We'll certainly look at Danario," Spagnuolo said. "He's excited about doing it. We want to make sure he's OK physically."
The Rams are coming off a game in which they surrendered 44 points to the previously winless Lions after giving up only 52 in their first four games.
"I'm disappointed in the loss and I'm really upset the fact that how we lost and by how much and all of that," Spagnuolo said. "These guys feel the same way, so we're in here trying to get it corrected."