I guess 54-10 barely makes the 10-year cut, so I'll put that one at No. 1.
But right behind it at No. 2 has to be the loss to USU in 2014. BYU was undefeated and ranked, Taysom Hill was a Heisman hopeful and looked like superman, and we were finally retiring Jim McMahon's number and putting him in the BYU Hall of Fame. It was set up to be a magical, celebratory night.
Then a crappy Utah State team came into town and completely demolished us with their backup QB. They broke Taysom's leg (or ankle or whatever), intercepted Christian Stewart three times, beat us by 15 and completely ruined our season.
I can't remember ever feeling worse after a BYU loss (other than the aforementioned 54-10 game).