Kevin Harvick, the 2014 winner of the Southern 500, leads the 2016 version of the race at the halfway point.
Harvick, the pole-sitter, has led 137 of the first 184 laps at Darlington Raceway.
Keselowski led 47 laps before Harvick retook the lead on Lap 140.
The first caution waved during green flag stops on Lap 95 when Trevor Bayne spun attempting to enter pit road. Bayne has since gone to the garage.
Jimmie Johnson runs in 22nd, a lap down after serving two penalties, including a pass through for a crew member altering the body of the car.
The second caution was caused when Brian Scott spun exiting Turn 2 on Lap 114.