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."
Source: Autosport