Houston quarterback Case Keenum is out for the season after injuring his knee in a loss to UCLA.
The Cougars also lost Keenum's backup, Cotton Turner, for the season Saturday night with a broken collar bone.
Keenum, the fifth-leading passer in NCAA history, tore his anterior cruciate ligament trying to make a tackle after an interception in the second quarter of the 31-13 loss.
Turner broke his clavicle in the third quarter.
"I am very disappointed for both these young men," coach Kevin Sumlin said in a release Sunday. "It's hard to see them hurting right now. They both are a big part of this team and wanted to be contributors to its success this season. I think they can still do that with their off-the-field leadership."
Keenum, a senior, came into the season as a Heisman Trophy hopeful, and the Cougars were considered among the favorites to win Conference USA after reaching the league title game as the West Division winners last season.
Keenum passed for 636 yards and five touchdowns in three games and had a good chance to break two major passing record if he could repeat last season's numbers of 5,671 yards and 44 touchdown passes.
He was 3,486 yards behind Timmy Chang's mark of 17,072, set from 2000-04 with Hawaii, and needed 28 more touchdown passes to break the record of 134 set by Graham Harrell of Texas Tech from 2005-08.
Keenum sustained a concussion last week trying to make a tackle after an interception against UTEP.
The Cougars will likely go with freshman Terrance Broadway in the wake of the injuries.