The homers included the go-ahead three-run shot off St. Louis closer Jason Isringhausen in the ninth inning.
Griffey also hit a solo shot to center field with one out in the fifth inning. It was the 43rd ballpark in which Griffey has homered, tying Fred McGriff for the major league record. Griffey, who has homered in every existing ballpark, has 546 home runs in his career.
However, it was his 10th of the season that catapulted Cincinnati to its fifth straight victory.
Griffey finished the night with three hits, all for extra bases, bringing his career total to 1,018, passing Mike Schmidt (1,015) into 22nd place on the all-time list.
Felipe Lopez had four hits, drove in two runs and scored twice for the Reds in the opener of the three-game series.