Matt Cain left after five innings with a 3-1 lead Saturday night.
Then the wheels fell off for the Giants as the Padres scored eight runs in the sixth and went on to win 12-4 at AT&T Park.
Reliever Chris Stratton gave up give earned runs in the sixth while Neil Ramirez was charged with the final three. He gave up three more in the seventh on a three-run homer by Allen Cordoba.
Cory Gearrin settled things down with two scoreless innings.
The Giants scored three runs off Padres starter Jhoulys Chacin in the fifth. Eduardo Nunez drove in Conor Gillaspie with a single to center. Four batters later, Brandon Belt singled to center plating Nunez and Kelby Tomlinson.
With the Giants trailing 9-3 in the bottom of the sixth, Gorkys Hernandez got a run back with a RBI-single to center.
The Padres and Giants wrap up the three-game set on Sunday. First pitch is scheduled for 1:05pm. Coverage begins at 12pm with Pregame Live on NBC Sports Bay Area.