USC easily reclaimed the Jeweled Shillelagh after two straight losses to the Irish, piling up 577 yards against Notre Dame's injury-plagued defense.
With Kessler's second-half scoring throw to Randall Telfer, Notre Dame yielded six touchdown passes for the first time in the program's 127-year history.
That defensive low caps a miserable second-half slide for the Irish (7-5), who have lost five of their last six games.
Everett Golson struggled mightily before Malik Zaire replaced him late in the first half with Notre Dame already trailing by 35. Zaire led a scoring drive and finished with 170 yards passing, providing hope for Notre Dame's future.
But the present in this rivalry belongs to the Trojans, who rebounded from their lifeless effort last week in a blowout loss to UCLA in their other big rivalry game.
"These guys have been such a resilient group all year," said USC coach Steve Sarkisian, who won his first shot at Notre Dame. "They have been through so much, and they keep working."
Kessler, who went 32 for 40, also became the first quarterback to throw five touchdown passes in a half against Notre Dame while completing 16 straight passes in a stretch spanning halftime.
After setting his career high in completions, the junior finished the regular season with 3,505 yards passing and 36 TDs against just four interceptions.
Before the final regular-season game of its NCAA sanctions era, USC said farewell to a small senior class. Several upperclassmen left with memorable games: J.R. Tavai matched his previous season total with 3½ sacks, including a fourth-down sack with 4 minutes to play, while Gerald Bowman had an interception and Hayes Pullard recovered a fumble as USC built its lead.
Greg Bryant rushed for 79 yards and a late TD for Notre Dame.
The low stakes didn't matter to fans as USC and Notre Dame closed out two disappointing regular seasons on a brilliant sunny day at the Coliseum, which hosted the schools' first meeting on Dec. 4, 1926.
Obviously aware of Notre Dame's injury woes on defense, USC opened the game at a high offensive tempo, running the ball right at the depleted Irish front. After a TD throw was overturned on video review in USC's first drive, Kessler hit Farmer in stride for a beautiful 48-yard TD moments later.
Jackson, USC's two-way freshman star, came out of the backfield for a 16-yard TD catch before Farmer capped the first quarter with a 31-yard TD catch down the seam.
Rogers and Agholor caught scoring passes while USC ran away from Notre Dame, which mounted nothing on offense with Golson behind center. Zaire sparked the Irish, getting a 49-yard completion on his first collegiate throw before rushing for an 11-yard score shortly before halftime.
Jackson sat out the second half with an apparent concussion.