USC linebackers Cameron Smith of Granite Bay High School and Lamar Dawson are out for the season with injuries.
Interim coach Clay Helton announced the prognosis for both players Saturday night.
USC (7-3, 5-2 Pac-12) beat Colorado 27-24 Friday for its fourth consecutive victory under Helton.
Smith leads the Trojans with 78 tackles as a freshman, making three interceptions and growing into a starring role. He was injured in the second quarter in Boulder, limping off the field with a torn ligament in his knee.
Dawson has a shoulder injury, Helton says. The senior has 31 tackles in eight games, ending his up-and-down career with another major injury after missing half of the 2013 season and all of 2014 with a knee injury.
USC finishes the regular season against Oregon and UCLA.