"That was probably the most fun game I've ever been a part of," Jackson said. "The crowd was loud, and we were having so much fun out there."
Sam Darnold passed for 205 yards and two TDs, and Ronald Jones II rushed for 134 yards and an early score to keep the surging Trojans in line for a New Year's Day bowl berth.
Josh Adams ran for 180 yards and DeShone Kizer passed for 220 yards and two scores for the Fighting Irish (4-8). They finished their worst season since 2007 with their largest margin of defeat this year.
With an unbeaten run through October and November, USC completed a perfect home schedule and remained in contention for the Pac-12 title. If Utah beats Colorado later Saturday, the Trojans will face Washington in the conference title game next week. USC fans repeatedly chanted "Let's go, Utah!" starting in the first half.
"What an accomplishment by a group of kids that have been through some adversity and come out the other side of it," USC coach Clay Helton said. "What this team and this group have is something special."
Jackson is expected to head to the NFL next year, but the junior put on one more exhibition of his singular talent at the Coliseum. USC fans chanted "One more year!" throughout the second half at a smiling Jackson, who has scored five touchdowns against Notre Dame in his career.
A mere 17 seconds after Jackson made his 55-yard TD punt return shortly before halftime, Ajene Harris returned an interception 33 yards for a score to break it open for the Trojans.
Jackson then turned a short pass from Darnold into a 52-yard TD with his world-class sprinting speed in the third quarter. He took a kickoff 97 yards for a score shortly afterward, hurdling the Notre Dame kicker at midfield and sprinting to the end zone to strike a Heisman pose.
JuJu Smith-Schuster caught a touchdown pass in the fourth quarter to punctuate the prolific junior receiver's own probable Coliseum finale.
Smith-Schuster is looking toward a bowl game, but also is thinking about the future.
"If Adoree comes back, I'm for sure coming back and we're going to win the natty," Smith-Schuster said, referring to the national championship.
Chris Finke, Kevin Stepherson and Equanimeous St. Brown caught TD passes for the Irish, who finished their dismal season with a series of mistakes and poor sportsmanship. Notre Dame defensive lineman Jerry Tillery made two particularly dirty plays in the second half.
Tillery first kicked USC running back Aca'Cedric Ware in the helmet while Ware was on the ground with an apparent head injury. Tillery wasn't penalized for that play, but got a tongue-lashing from his coaches, while teammate Nicco Fertitta was ejected for targeting.
Tillery then received an unsportsmanlike conduct penalty a few minutes later when he stomped on prone USC offensive tackle Zach Banner's foot.
"You just can't do stupid things like that," Notre Dame defensive lineman Jarron Jones said. "That's going to reflect on you as a player. That's going to reflect on your character."
Referee Ron Cherry left the game in the third quarter after getting flattened in an accidental collision with USC linebacker Michael Hutchings. Cherry appeared to be unconscious after hitting the turf, but eventually walked up the tunnel unaided.
Notre Dame: This was an embarrassing end to an uncommonly ugly year for the Irish. Coach Brian Kelly will find little to salvage from this trip to LA, and Tillery was already receiving heavy online criticism for his dirty play before the game ended.
USC: The Trojans have evolved into one of the nation's best teams over the last two months. It happened slightly too late to get into the national title conversation without some serious help, but Helton clearly harnessed USC's formidable talent heading into the postseason.
USC: Either an upper-tier bowl game or the Pac-12 title game in Santa Clara.