The Padres were trailing 1-0 in the ninth and facing fire-balling Cincinnati closer Aroldis Chapman (3-4) when Yonder Alonso coaxed a lead-off walk.
Then Denorfia, pinch-hitting for Wil Venable, blasted the first pitch he saw over the fence and straightaway center field, handing the Padres a comeback triumph.
Luke Gregerson (5-5) was credited with the win after starter Sean O'Sullivan, Joe Thatcher and Nick Vincent had combined for eight scoreless innings for San Diego, which took the opener of a three-game series.
Reds starter Mike Leake got a no-decision after hurling seven shutout frames, during which he scattered four hits, walked two and fanned five.
Cesar Izturis provided Cincinnati's only RBI.