Kenseth snapped a 17-race winless skid in the AAA 400 Drive for Autism with his 37th career victory, denying Larson his first win.
"I got digging the best I could and tried to hold him off," Kenseth said.
Kenseth and Larson battled door-to-door for part of the final five laps, and the 2003 NASCAR champion picked all the right lines and pulled away at the end. Chase Elliott made a late push and finished third in the No. 24 Chevrolet. Larson matched his career-best finish and Elliott had the top finish of his rookie season.
Kenseth joined his three Joe Gibbs Racing teammates in Victory Lane for 2016. The 44-year-old Kenseth is older than the combined ages of Elliott, 20, and the 23-year-old Larson. Larson said he had too much respect for Kenseth to try to bump out of the way when they closed within a few inches of each other.
"I was trying to do all you could do to get by him without getting into him," Larson said.
Kenseth, Larson and Elliott were among the survivors after Jimmie Johnson triggered a late-race crash that eliminated several contenders.
He was responsible for a pileup straight out of the Talladega highlight reel that knocked out a slew of drivers who raced up front all race and brought it to a halt with fewer than 50 laps left.
Johnson, a 10-time winner at Dover, failed to jump off the restart because of a faulty transmission in the No. 48. The six-time champion could not shift the Chevy into third gear and 18 cars -- stacked and off at full speed -- were collected in the melee.
He was leading in the outside lane as he closed in on the start-finish line. Martin Truex Jr. nailed the 48 from behind and Dover soon looked like the site of a gnarly demolition derby.
"In my career, I've never had a transmission do that to me," Johnson said.
Truex, Kevin Harvick, Dale Earnhardt Jr., and Kyle Busch were among the drivers whose cars piled up on the concrete.
Truex led 47 laps and seemed poised to earn his first win of the season.
"I want to get out and punch somebody," Truex said over the radio. "Seriously. Hard. Like, as hard as I can."
Busch, the reigning series champion, knew there was nowhere for the 18 to go but into the pile.
"Wait for me, I'm coming," he said.
Aric Almirola said he suffered a broken finger in the wreck.
The race was stopped for 11 minutes, 22 seconds -- and quickly had another caution shortly after it resumed. Carl Edwards suffered a brutal blow when the No. 19 slammed nose-first into an inside wall protected by SAFER barriers. Larson made contact with Edwards and shot the JGR driver into the wall.
That left Kenseth, Larson and Elliott, who deftly avoided the Johnson-led accident, in a three-car battle down the stretch.
Kasey Kahne was fourth and Kurt Busch fifth.
Kenseth holds of Larson to win at Dover
Matt Kenseth records his 37th career victory and third at Dover by holding off Kyle Larson in the final laps.