On a 2-0 count against Reds starter Micah Owings, Ramirez crushed a wayward slider into the left-field bleachers for career shot No. 537. After Ramirez circled the bases and retired to the dugout, the crowd serenaded him with chants of "Manny! Manny!"
While the fans reacted to the blast with thunderous applause, Ramirez brushed off the historic home run after the game.
"To be honest I haven't been keeping track of who I've passed or where I'm at. I just wait for you guys to tell me," Ramirez told reporters after the game. "So I'm glad I'm moving up."
Ramirez has 10 home runs on the year, four since his return from a 50-game suspension for violating the Major League Baseball drug policy.
Next up on the career home run list for Ramirez is Mike Schmidt at No. 14. Schmidt hit 548 home runs in his career.
"I'm going to look back later on and see what I accomplish, but I want to take it day by day and move to the next day," Ramirez said.
David Ely is an associate reporter for MLB.com. This story was not subject to the approval of Major League Baseball or its clubs.