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.
Members of Congress to keep receiving porn magazine
Putin thinks Obama would save him if he were drowning