In the first inning of Saturday afternoon's game at Great American Ball Park, Griffey connected on a 3-1 pitch from Braves right-hander Jair Jurrjens and sent it sailing 380 feet into the right-field Sun Deck.
The 599th home run of Griffey's career, which followed Jay Bruce's single, put the Reds ahead, 2-0.
"He's been swinging the bat great," said Reds manager Dusty Baker. "That was a rocket hit out there. He's been hitting line drives. Sooner or later, he was going to elevate one."
Griffey was unavailable for comment following Saturday's game.
Jurrjens is the 383rd pitcher against whom Griffey had homered.
It was Griffey's second home run since snapping a 90-at-bat homerless streak on May 22 at San Diego.
It was his eighth home run off the Braves, and his 64th hit at Great American Ball Park.
With his next home run, Griffey will become just the sixth player in Major League history to collect 600 career home runs.
Baker has witnessed his share of milestone home run pursuits.
He was a teammate of Hank Aaron during his chase of Babe Ruth's mark. Baker also managed Barry Bonds and Sammy Sosa during their pursuit of homer milestones.
Baker's advice to Griffey is to relax and have fun.
"It's great, it's exciting," Baker said. "They're changing the balls to [authenticated] Griffey balls. That's OK. He just needs to center the ball. He needs to enjoy it."
Jeff Wallner is a contributor to MLB.com. This story was not subject to the approval of Major League Baseball or its clubs.