According to Sarkisian, Wheeler tore his ACL on the third play of the game, but stayed on the field and played a few more plays before taking himself out.
Wheeler is a redshirt sophomore who has started all 22 of the Trojans' games since last season.
Sarkisian praised Wheeler's endurance and said that his coaching staff was not initially aware of his injury.
"He fought through it until he just couldn't anymore," Sarkisian told reporters. "That's the biggest thing we lose without him being out there."
The 6-foot-7, 275-pound Wheeler has spent his career thus far on the Trojans' left side. USC, 4-2 in the Pac-12 and 5-3 overall, is currently fourth in the Pac-12 South, behind third-place Utah (3-1, 6-1).
Senior Aundrey Walker, who has started 18 games as a tackle and guard, took over at left tackle once Wheeler left the game.
Walker will start Saturday on the road against Washington State (1-4, 2-6).