Griffey launched a 2-0 pitch from Houston right-hander Chris Sampson into the right-field stands for career homer No. 597.
Griffey's solo homer, which traveled an estimated 424 feet, put the Reds ahead 1-0.
It was his 199th home run in a Reds uniform, moving him into sole possession of eighth place on the franchise's all-time home run list ahead of former shortstop Barry Larkin.
Sampson is the 381st different pitcher off which Griffey has homered.
Jeff Wallner is a contributor to MLB.com. This story was not subject to the approval of Major League Baseball or its clubs.