The loss dropped Cincinnati 3 1/2 games behind San Diego in the NL wild-card race. The Reds are 5-12 since moving within one percentage point of St. Louis in the NL Central on Aug. 24. They are now five games behind the Cardinals in the division.
Peavy (9-14) is 4-0 in six career starts against Cincinnati. In his only previous start against the Reds this year, he pitched a two-hitter in the Padres' 7-1 victory Sept. 2 in San Diego.
He allowed three hits over six innings on Wednesday.
Geoff Blum had a two-run homer and also doubled twice in the Padres' 16-hit barrage. Brian Giles and Adrian Gonzalez also had a pair of RBIs apiece.
Reds starter Kyle Lohse (2-3), also the loser in that Sept. 2 game, allowed seven runs and eight hits in 2 1-3 innings.
A four-run second inning, which included an RBI double by Peavy, drained the game of any drama that remained from the Reds' Tuesday night walk-off win that had shaved a game off San Diego's lead in the wild card race.
The Reds had offered reduced price tickets and $1 hotdogs in an effort to draw fans for this crucial series. Attendance was announced as 21,602.