Larson grabbed control of the race late in the final stage, when he was first off pitroad after the field came in during a caution caused by Ryan Newman spinning off at Turn 4.
Larson led on the restart with 51 of 367 laps remaining, then held on through two more late-race restarts.
Reddick moved into second on the final restart with 31 laps to go and initially challenged Larson for the lead, but the 2021 NASCAR Cup champion was able to edge him by 0.447 seconds to earn his first Southern 500 victory.
“Finally [we executed] from start to finish,” Larson said. “Going 18th to third in the first stage, I didn’t think that was possible but our car was really good when the sun was out. Just had to work on it. I messed up once and it got hung in neutral, and I slid and hit the wall, and I think bent the toe link a little bit, so it was kind of a struggle from there.
“Definitely had to fight it more than I was earlier, but we kept our heads in the game. That was really important. This race is all about keeping your head in it. I’ve been pretty hard on myself here the last couple months, but having a leader like Cliff [Daniels, crew chief], he really is good for my mind.
“What a great way to start the playoffs and hopefully we can keep it going.”
Tyler Reddick, 23XI Racing, Jordan Brand Toyota Camry, Denny Hamlin, Joe Gibbs Racing, Sport Clips Haircuts Toyota Camry, Kevin Harvick, Stewart-Haas Racing, Mobil 1 Take 5 Ford Mustang, Kyle Larson, Hendrick Motorsports, HendrickCars.com Chevrolet Camaro, Chase Elliott, Hendrick Motorsports, NAPA Auto Parts Chevrolet Camaro, Ryan Blaney, Team Penske, Menards/Richmond Water Heaters Ford Mustang
Photo by: Matthew T. Thacker / NKP / Motorsport Images
Larson entered the playoffs as the sixth seed, with two wins notched up at Richmond and Martinsville both taken back in April, but heads to Kansas next weekend second in the playoff standings behind Hendrick Motorsports team-mate William Byron.
The key for Larson was to stay out of trouble, which is what several playoff drivers experienced in the race, including Denny Hamlin, who won both stages and led 177 laps.
But Hamlin’s night went wrong when he was forced to pit twice under green for what he thought was a loose wheel. He later got caught up in an accident and finished 25th.
Chris Buescher finished third, Byron took fourth and Ross Chastain rounded out the top five. With playoff contenders Brad Keselowski and Bubba Wallace in sixth and seventh respectively, it was the first non-playoff runner of Chase Elliott in eighth place.
Ryan Blaney, also in the playoffs, was ninth ahead of Erik Jones, who isn’t in the playoffs, who rounded out the top 10.
With two races remaining in the first round of the playoffs, Wallace, Kevin Harvick, Ricky Stenhouse Jr and Michael McDowell are the lowest drivers in points without a win and in danger of being eliminated from further title contention.
It was an especially tough race for McDowell who failed to finish having been collected in a Kyle Busch wreck with 31 laps to go.
NASCAR Cup Darlington race results (367 laps)