Busch started from the pole Friday night and led 228 of the 250 laps en route to the 60th series win of his career. It made him 2 for 2 so far this week at Bristol, where he won Wednesday night's Truck Series race.
Brad Keselowski finished second and was followed by Austin Dillon and Justin Allgaier.
Kyle Larson was fifth, while Trevor Bayne was sixth and followed by Ty Dillon and Kasey Kahne. Brian Scott and Elliott Sadler rounded out the top 10.
Sam Hornish Jr. entered the race as the Nationwide Series points leader but had a spark plug wire problem and finished 12th.