The Padres sailed into St. Louis on a modest two-game winning streak and left totaling just six runs over 27 innings.
Venable sparked an early outburst with a leadoff homer to start his 3-for-5 performance. Vrenable is 18-for-41 in St. Louis in his career and has turned in some of his best offensive performances in the shadow of the Gateway Arch.
"I can't explain it, there are just some places where you see the ball better," Venable said. "It's nice to feel comfortable in a place."
Venable got the offense off to a quick start by smashing the second pitch of the game from Lance Lynn over the wall in right. The Padres then built a 3-0 lead on Lynn's first 21 pitches.
Following Venable's sixth career leadoff homer, Cameron Maybin drilled a base hit up the middle and Yonder Alonso drew a walk. Chase Headley, returning to the lineup after sitting out Tuesday with a minor muscle strain in his back, singled to make it 2-0. Nick Hundley brought in the third run with a groundout.
But Lynn and three relievers shut the door the rest of the way. San Diego managed seven hits over the final eight innings, but could not score.
"As an offensive club, we've got to find a way to get it back going again," Headley said.
San Diego manager Bud Black was pleased with the early onslaught. He just wanted to see more offense later in the game.
"Obviously, when your leadoff hitter goes deep, it sends a nice feeling of confidence through the dugout," Black said. "We really jumped out. But after that, Lynn got a little stingy."
Venable added a single in the second and a double in the fourth. He came up one hit shy of a cycle for the fifth time in his career. He was a home run short of the honor in a 6-1 win at Washington on May 15.
"As the game goes on, it's more about the game than a cycle," Venable said. "We play to win the game. Cycles are cool if they end up happening."
San Diego right-hander Jeff Suppan struggled in the first and lasted just 4 2/3 innings. He gave up five earned runs on eight hits against his former team. Suppan played a key role in the Cardinals' drive to the 2006 World Series championship.
Suppan walked four and gutted his way through three successive scoreless innings before Carlos Beltran broke a 3-3 tie with a two-run homer in the fifth.
"The offense did a great job scoring early and I needed to do a better job in that first inning," Suppan said. "I thought we had a good game plan. The execution was there for some pitches, but for others it wasn't."
Beltran picked on a cut fastball and drove it 411 feet.
"I thought that was the right pitch to Carlos," Suppan said. "Obviously not. He did a good job staying inside the cutter."
San Diego put a pair of runners on in the sixth on singles by Everth Cabrera and Maybin. But Lynn got Alonso to fly to center to end the threat. Cabrera broke out of an 0-for-19 skid with the single.
The Padres got hits from Hundley in the seventh and Cabrera again in the eighth but could not come up with the timely hit. They stranded 10 runners and were 1-for-8 with runners in scoring position.
"We just couldn't mount anything after that first inning," Black said. "Their bullpen did a nice job."
David Freese added a solo homer off Brad Brach in the seventh to give the Cardinals a 6-3 lead.
Alonso has reached safely in 22 of his last 25 games.
Reliever Miles Mikolas did not allow a hit in 1 1/3 innings of relief. He struck out two.