Toms and Villegas shot 9-under 63 to top a leaderboard dotted with impressive scores in the opening round Thursday.
Villegas and Toms both played bogey-free at the erstwhile Bob Hope Classic, which has dropped one day of its traditional five-round format this year.
After playing on the winning U.S. team in the Presidents Cup, Toms passed on a hard-to-get spot in the lucrative Chevron World Challenge in December to spend extra time with his family. He shook off an unimpressive start to the new season in Hawaii with excellent play alongside Presidents Cup teammate Phil Mickelson at La Quinta Country Club, which features the tournament's toughest course.
Toms also got a boost playing alongside Mickelson, who struggled to a 74. Toms made a 30-foot birdie putt on the sixth hole right after Mickelson holed an eagle putt, ratcheting up the energy in an often staid tournament.
"That's probably the biggest crowd I've ever had playing golf here," Toms said. "It was nice to play a good round and have people energized and out there cheering for your birdies."
Villegas recovered from his disappointing 2011 with an extended break in his native Colombia and Florida. In his tournament debut, he made nine birdies in his first crack at the Nicklaus Private course, coasting through a round he could barely recall after he finished it.
"You feel that you're a little rusty, but at the same time, you're mentally fresh," said Villegas, a three-time PGA Tour winner. "It's a funny game. Sometimes being mentally fresh is more important."
The Humana Challenge has been invigorated by multiple changes including its new title sponsor, an increased purse and a partnership with the Clinton Foundation to promote healthy lifestyles. Bill Clinton, who will play alongside old friend Greg Norman on Saturday, showed up to the event Thursday.
Enthusiastic crowds also showed up in the Coachella Valley to cheer on an improved field including Mickelson, defending champion Jhonattan Vegas and world No. 8 Dustin Johnson, who matched Norman at 72 in the Shark's first Palm Springs appearance since 1986.
Toms and Villegas aren't the only players using the week to round into form for bigger challenges ahead. Rough spots in their games are more easily fixed in Palm Springs' perfect weather -- although rain could be headed to the valley for the weekend.
"Nothing really worked," Norman said after his first PGA Tour start since 2009. "It was just pure rust, that's all it was. Just rusty, rusty, rusty."
Potter made five consecutive birdies after the turn in his round, while the 45-year-old Estes, who hasn't won since 2002, finished with consecutive birdies to move into a third-place tie.
Another change to the tournament was an immediate hit with the pros: Instead of playing with three amateur partners in each of the first four rounds, two pros are teaming with two players, which makes for more fun.
"I've looked at the pairings, and I can tell that a lot of guys are playing with their friends and other golfers, the guys that are close," said Toms, who counts Mickelson as a close friend.