"That final pit stop, my guys really put the pressure on them knowing how good they'd been on pit road all night," Busch said after his fourth career victory at Richmond International Raceway.
Edwards came back out fourth, and while he and Ricky Stenhouse Jr. battled for position, Busch was able to pull away and win by 0.696 seconds.
Busch's victory was his 51st in the series, the most in history, and came in a race he and Edwards dominated on the 0.75-mile oval. Edwards led 160 laps, Busch 74, including the last 34.
The two Sprint Cup Series regulars have won 14 of the 27 races in the series this year.
While Busch thanked his pit crew for a "flawless job," Edwards refused to blame his for the issue that caused him to lose three spots after heading for pit road with the lead.
Stenhouse, who was running second when the race went back to green with 30 laps to go, thought he could have made a better challenge to Busch, but fell short.
"I thought we had a little bit for Kyle there at the end. It started off really good. We were kind of running him down and then just lost forward grip," Stenhouse said.
That allowed Edwards to pass Stenhouse, but he, too, ran out of time.
"I wish we had one more caution, got another shot at him," Edwards said, while also crediting Stenhouse for letting him make a run at the leader.
"He didn't hold me up when I was coming there at the end," Edwards said. "Those guys earned it. They got faster all night. We had a little bit of trouble. It is like our car went away just a little bit."
Keselowski, the pole-sitter, was already out of contention and finished 19th.