Busch led the last 40 laps at the Infineon Raceway and was in front 78 laps overall.
The win was the ninth of Busch's Sprint Cup career. It gave him a 103-point lead over Jeff Burton in the cup standings.
Busch twice made pit stops prior to a caution flag, helping him keep the lead. He praised his pit crew.
"These guys worked so hard," he said. "This is really special. We came a long ways with this thing. That's what makes me so proud of this team."
Jeff Gordon, Bowyer and Casey Mears finished 3-4-5.
The next race is June 29 at the New Hampshire International Speedway.