D-backs starter Wade Miley barely broke a sweat before the Padres had a lead.
"They are a very aggressive team and he got behind early and had to come over the plate in the first inning," D-backs manager Kirk Gibson said.
Chris Denorfia led off the game with a single to left and scored when Will Venable followed with a double to right-center.
"Really the worst one was the one to Venable," Miley said. "I thought it was maybe up a little bit, but I was behind in the count and tried to throw a strike. It was away on the black a little bit. He did a good job of hitting it."
Two outs later, Jesus Guzman delivered an RBI single and the Padres led, 2-0.
And then, well, that was it for the Padres for the next six innings as Miley kept them off the board before departing for a pinch-hitter in the seventh.
Miley said he didn't make any real adjustments after the first, it was just a matter of the Padres not hitting his good pitches after that.
"I thought I made some pretty good pitches in the first, they did a good job of putting the ball in play, hitting some balls hard and that's just the way it goes," Miley said.
The two runs proved to be enough, though, because the Arizona hitters could not solve San Diego pitching on this night.
First it was Robbie Erlin, who was recalled earlier in the day from Triple-A Tucson to make his first big league start since July 7. In that game he allowed nine runs to the Nationals.
Erlin, though, kept the D-backs off the board through the first five innings.
"He hit his spots, he's a guy that keeps you off-balance," D-backs outfielder Adam Eaton said. "He has a very good curveball, comes out of his hands very well."
The D-backs finally broke through for a run in the sixth when Eric Chavez got it started with a two-out walk. After Aaron Hill singled, Willie Bloomquist delivered an RBI single to right to cut the lead to 2-1.
Erlin (2-2) allowed six hits over his six innings to earn the win.
"He threw good, he had a fastball, curveball and some changeups," Gibson said. "He threw to both sides of the plate, he just threw the ball well."
The D-backs had a chance in the seventh off reliever Tim Stauffer, but with runners on first and second and one out, Eaton and Martin Prado could not come through with hits as Stauffer escaped the jam.
"We had some opportunities but we didn't get the big extra-base hit when we needed it," Gibson said.
The Padres added some insurance runs in the eighth against D-backs reliever Heath Bell.
Denorfia singled to lead off the inning and Venable then hit a hanging breaking ball into the right-field seats to give San Diego a 4-1 lead.
Venable was 2-for-4 with a double, a homer and three RBIs.
"Will is doing a good job of capitalizing on the high breaking ball," Padres manager Bud Black said. "He's not missing it. Pitches that are up, when guys square them up, it's a damage pitch."
Guzman added a solo homer later in the inning off Bell, who like most of the Arizona relievers, has pitched a lot of late.
"He's gassed, but so is everybody else," Gibson said. "He threw a pitch down and in to Venable and that's his nitro zone. The one to Guzman, they are a first-pitch-hacking team, so if you throw a first-pitch fastball like that, they are going to swing."
It was the first loss for Miley (9-9) since July 20.