Coach Lane Kiffin announced Sunday that freshman Max Wittek will make his first career start in place of Barkley.
Barkley was injured in the final minutes of the Trojans' 38-28 loss to UCLA when he was sacked by linebacker Anthony Barr. Barkley stayed down on the field for a long moment, and Wittek replaced him on USC's final series.
"I feel bad for him and his family," Kiffin said. "This is obviously not how you want it to be."
A four-year starter at USC, Barkley was a strong Heisman Trophy candidate last season and again this summer after electing to return for his senior year. Instead, his final season at USC has been just as inconsistent as the Trojans (7-4, 5-4 Pac-12), the preseason's No. 1 team.
USC dropped out of the Top 25 on Sunday after its third loss in four games. The No. 15 Bruins held on at the Rose Bowl for just their second win over the Trojans in 14 years.
Barkley has passed for 3,273 yards and 36 touchdowns, but has thrown a career-worst 15 interceptions. He became the career leader in multiple statistical categories at USC and in conference history, yet his decision-making and accuracy have been spotty at times.
But Barkley has been a steadfast leader throughout the Trojans' recovery from crushing NCAA sanctions, speaking for his teammates during the program's roughest times. He had been looking forward to his first chance to face Notre Dame at home before the Trojans' bowl game.
Barkley will miss just the third game of his USC career, but his second against Notre Dame. He also sat out the Irish's visit to the Coliseum in 2010 with a sprained ankle, and backup Mitch Mustain led the Trojans to a 20-16 loss - but only after Ronald Johnson dropped a sure touchdown pass from Mustain with 1:22 to play.
Kiffin doesn't yet know whether Barkley will be able to play in the Trojans' bowl game. The quarterback sprained an AC joint in his shoulder, and the team doesn't know the severity of the injury.
The 19-year-old Wittek is from the same hometown (Newport Beach, Calif.) and high school (Mater Dei) as Barkley. Wittek has played sparingly this season as a freshman after winning a competition with Cody Kessler to be Barkley's backup.
Wittek has completed eight of his nine passes this season for 95 yards and one touchdown.