Larson grabbed control of the race late in the final stage, when he was first off pit road when the field pit during a caution caused by Ryan Newman spinning off Turn 4.
Larson led on the restart with 51 of 367 laps remaining, then held on through two more late-race restarts in the final 47 laps.
Reddick moved into second on the final restart with 31 to go and initially challenged Larson for the lead but Larson was able to edge him by 0.447 seconds at the checkered flag 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 race 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."
Larson, 31, entered the playoffs as the sixth seed behind two wins but heads to Kansas Speedway next weekend now second in the playoff standings behind Hendrick Motorsports teammate 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.
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 was fourth and Ross Chastain rounded out the top five.
Completing the top-10 were Brad Keselowski, Bubba Wallace, Chase Elliott, Ryan Blaney and Erik Jones.
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.
Stage 1
Hamlin ran down Reddick for the lead with 24 laps to go and held on for the Stage 1 win as Wallace spun off Turn 4. Larson was third, Harvick fourth and Blaney fifth.
Stage 2
Hamlin held off Larson by 0.509 seconds in a one-lap dash following a late caution to claim the Stage 2 win. Jones was third, Reddick fourth and Byron rounded out the top five.
NASCAR was forced to throw a caution on lap 179 and red-flagged the race for nearly seven minutes to repair the inside lights in Turn 3, which went dark.
Austin Cindric and Ty Gibbs wrecked in Turn 2 to set up a one lap restart to the finish.
CAUTION!
— NASCAR on NBC (@NASCARonNBC) September 4, 2023
Austin Cindric drives up into Ty Gibbs! #NASCAR pic.twitter.com/k4lewV42nU
Stage 3
Following the break between Stages 2 and 3, several lead-lap cars elected to pit but Hamlin stayed on the track and remained in the lead when the race resumed with 131 laps remaining.
With 100 laps to go, Hamlin maintained the lead but had Reddick, Byron and Harvick in close pursuit as Kyle Busch kicked off another round of green flag pit stops.
After completing his stop, Hamlin reported a loose wheel on his No. 11 Toyota and was forced to pit a second time under green. He returned to the track in 30th and scored one lap down.
Shortly afterward, Hamlin’s crew chief, Chris Gabehart told his driver, “Wheels looked fine.”
With under 60 laps to go, Harvick closed to second behind Reddick and dove onto pit road for his final green flag pit stop just as Newman spun out off Turn 4 to bring out a caution. Harvick ended up pitting on a closed pit road, which drew a penalty.
When the rest of the field pit, Larson was first off pit road and took over the lead when the race resumed with 51 laps remaining. Harvick lined up 26th on the restart.
Three laps later, Alex Bowman and Daniel Suarez wrecked in Turn 1 in an incident that also collected Harrison Burton and brought out the seventh caution of the race.
A bad block!
— NASCAR on NBC (@NASCARonNBC) September 4, 2023
Alex Bowman, Daniel Suarez and Harrison Burton all crash! #NASCAR pic.twitter.com/GS5t9Zyku7
A handful of lead-lap cars pit but Larson remained on the track and in the lead on the restart with 40 laps to go.
Busch got loose and triggered a multi-car wreck on the frontstretch that collected Todd Gilliland, McDowell, Bell and Hamlin that sent up another restart with 31 laps remaining.
