Coach Scott Linehan said Sunday that Setterstrom, a seventh-round pick in 2006 who has made nine starts in two seasons, would have surgery later in the week.
Quarterback Marc Bulger, who hurt his shoulder when hit from behind while preparing to throw in the second quarter, was believed to be fine. Linehan said team doctors were not concerned.
"We'll just see how he feels throwing tomorrow, if he can," Linehan said. "From my standpoint I think he's going to be just fine."
Bulger was taken out of the game after the hit because he could not have taken the next snap, but characterized it as a "five-minute thing" after the game.
Setterstrom tore a ligament and damaged cartilage in the same knee in the third game of the season last year, finishing that year on IR. He began training camp this summer as the starting right guard but was a reserve on Saturday against the Chargers after missing time with a strained muscle near his right knee.
Another offensive lineman, Brandon Gorin, will also be placed on injured reserve with a shoulder injury sustained in the preseason opener at Tennessee. Gorin made eight starts at tackle and played in 11 games last year, filling in when three line starters ended the year on injured reserve.
"There's some pretty significant damage that didn't show up on the first MRI," Linehan said.
Running back Brian Leonard sprained his shoulder on Saturday and Linehan said he would be "pretty iffy" for next week's preseason game against the Ravens. Linebacker David Vobora has a severely sprained ankle and could miss the last two preseason games.