Headley finished 4-for-5 for the NL West-leading Padres, who were coming off a 3-3 homestand that included a series win over the Dodgers. Yorvit Torrealba extended his hitting streak to 15 games by going 3-for-5.
San Diego starter Clayton Richard (9-5) got the victory after laboring through 5 1/3 innings, in which he threw 105 pitches. Richard allowed four runs on 10 hits and three walks, and struck out six.
"I thought I had a pretty good outing, but the numbers may not show it," Richard said. "Every time we play a division rival, we try to take care of business."
Dodgers starter Hiroki Kuroda (8-10) allowed five runs -- four earned -- in four innings to take the loss, while Jeff Weaver gave up five runs over the next two frames to put the game further out of reach.
Matt Kemp had a career-high five hits for the Dodgers, who had 14 hits overall, but only two for extra-bases -- Kemp's double and home run. Kemp had three total RBI for Los Angeles, which has lost six in a row to match a season high.
"You make your own breaks," Dodgers manager Joe Torre said. "We have to start doing things right. Our confidence level is not good right now. We got more hits tonight, we just couldn't keep the other team from scoring."
San Diego never trailed and took control with a five-run fourth inning. After Headley and Torrealba reached on singles, Venable hit a sinker to right-center field for his ninth homer of the season.
Chris Denorfia followed with a single and Richard attempted a sacrifice, but Russell Martin's throwing error allowed the runners to advance into scoring position. Miguel Tejada made it a 5-0 game with a two-out single, recording his first two RBI for the Padres since coming over from Baltimore in Thursday's trade.
Los Angeles got two of the runs back on run-scoring singles from pinch-hitter Ronnie Belliard and Kemp, but the Padres' offense was back at it in the fifth.
With Weaver on the mound, Ryan Ludwick singled and Headley doubled. Torrealba's infield single brought in Ludwick, while Venable's sacrifice fly plated Headley for a 7-2 lead.
Headley again helped to push the advantage in the sixth. With two on and two away, he hit his eighth homer of the year to center field.
Richard was removed with one out and runners on the corners in the bottom half of the inning, and was replaced by Ryan Webb. Rafael Furcal and Kemp hit RBI singles to get the Dodgers within 10-4, but James Loney followed with a line out, and Kemp was doubled off first to end the inning.
Headley recorded his third four-hit game of the season...The Dodgers fell to 5-13 since the All-Star break...LA went 6-for-18 with runners in scoring position and left 12 on base.