Chicago scored six times in the first inning, but ran into a wall against the San Diego bullpen.
Gyorko started the Padres comeback with a three-run homer in the fourth and Venable tripled in two runs in the fifth.
Another triple by Logan Forsythe in the sixth delivered the tying run, Venable homered in the seventh to put the Padres in front and Gyorko tacked on yet another home in the eighth.
The Cubs have lost four in a row and the Padres have captured four of six.
Nick Vincent (3-1), the fourth of six San Diego pitchers, picked up the win by working the seventh inning. Huston Street recorded his 24th save after giving up a two-out single in the ninth.
James Russell (1-6) gave up the go-ahead run in the seventh during his only inning of work to take the loss.