Busch's No. 18 Toyota cruised to victory after he passed Clint Bowyer on lap 229, and he went on to capture his 13th career Sprint Cup Series victory at a track he had seen constructed when he was a youngster.
Busch won the pole Friday, but had to start the race from the rear because of an engine change.
"This is cool," Busch said during a post-race television interview. "Coming to the checkered flag I had knots in my stomach. This is probably bigger than winning the Daytona 500 (for me)."
The accident-marred race at the Las Vegas Motor Speedway featured a Sprint Cup single-race record 14 caution flags.