Reds shortstop Zack Cozart sent the first offering of the game from Giants starter Matt Cain over the wall in left, putting an abrupt end to San Francisco's four-game shutout streak.
Cozart's homer was part of a three-run opening frame, and Mike Leake tossed the first complete game of his career as the Reds downed the Giants, 5-1, in the second installment of a four-game set.
Leake (3-5), who also cracked a solo shot in the sixth, had his shutout bid halted in the ninth when Pablo Sandoval launched a solo blast. He gave up nine hits and a walk while striking out four.
"I'm sure he wanted the shutout, but we'll take 5-1," Reds manager Dusty Baker said.
Jay Bruce smacked a career-high four hits, which included a pair of doubles, to go with three RBI and Joey Votto added three hits and a run scored for Cincinnati, which had lost seven of its last 10 coming in.
Matt Cain (9-3) had his 10-start unbeaten streak snapped. He fanned seven and was charged with five runs on 11 hits and a walk over 6 2/3 innings for San Francisco.
During San Francisco's remarkable shutout stretch, Giants pitchers had not allowed a run in 36 innings. They fell two frames shy of matching the franchise's all-time mark, which is 38 set by the 1903 and 1933 New York Giants.
After Cozart's first career leadoff homer and first by a Reds player this year, Drew Stubbs walked and Votto double to deep left, putting runners on second and third. Bruce brought them both home when he belted a double to center for a 3-0 Reds advantage.
"It was big to get one across first," Baker said. "Right away we jumped them in the first inning."
The Reds padded their margin with a run in the sixth and another in the seventh.
Leake smacked his second round-tripper of the season in the sixth, while Bruce registered another RBI double in the seventh to make it a 5-0 game.
Sandoval pulverized a solo blast into the seats in right-center with one out in the ninth to conclude the scoring.
"You're going to have an off day," Giants manager Bruce Bochy said. "Today it happened"
Two of Cain's three losses this season have come against the Reds. He allowed three runs on five hits and two walks in 6 1/3 innings against them on April 24...The Reds snapped a four-game road losing streak...Cincinnati was 2-for-10 with runners in scoring position while San Francisco finished 0-for-8.