Leake outdueled one of the hottest pitchers in baseball, Shelby Miller, who hadn't lost a regular-season game since Aug. 11 of last season, a span of 12 starts.
Leake (1-1) limited Atlanta to two hits and two walks over eight scoreless innings. The Reds backed him with four home runs as a team, with all four coming in the seventh inning or later.
Miller (3-1) struck out nine batters, his highest total since June 2013, but took the loss after allowing three runs -- two earned -- on six hits over seven innings.
It took a passed ball for the Reds to finally break through for a run after five scoreless innings.
Billy Hamilton led off the visiting sixth and struck out swinging, but was safe at first on the play after catcher Christian Bethancourt dropped the pitch. Zack Cozart followed with a single to left and Joey Votto doubled to easily score Hamilton and make it 1-0.
Tucker Barnhart and Leake hit back-to-back home runs in the seventh inning. Todd Frazier stroked his second homer of the season in the eighth and Hamilton went yard in the ninth.
Leake didn't allow a hit after the second inning. Tony Cingrani pitched the ninth and served up Freddie Freeman's RBI double that broke up the shutout.
Leake became the first pitcher to hit a home run this season ... Atlanta has dropped three straight games ... Cincinnati finished 1-for-11 with runners in scoring position and stranded eight.