Kenseth beat Jeff Gordon to the checkered flag in his No. 17 Ford Fusion to become first NASCAR driver to win the first two races of a season since Gordon did it in 1997.
The victory gave Roush Fenway Racing its fifth straight win at Fontana.
Kenseth was the unexpected winner at the rain-shortened Daytona 500 last Sunday.
"I am so blessed I have such a great race team," Kenseth said after the 18th victory in his Sprint Cup career and third at the two-mile Auto Club Speedway. "They gave me a great pit stop that got me the clean air that was so important."
Kyle Busch, Greg Biffle and Kurt Busch completed the top-five finishers.
"When I caught him (at lap 232) I couldn't do anything with him," Gordon conceded. "He didn't make any mistakes."