Villegas's strong finish capped a sparkling round of 64 on the par-70 PGA National course, following four earlier birdies.
The 31-year-old, who won by five strokes here two years ago for the most recent of his three US titles, hit 10 of 14 fairways and 14 greens in regulation and produced nine one-putts.
Villegas had a one-stroke lead over Branden Grace of South Africa, Canadian Graham DeLaet and Americans Rickie Fowler and Robert Streb.
The six-under par round was a welcome return to form for Villegas, who missed nine cuts in 25 starts last season, lost his tour card and has missed two of three cuts so far this year.
The Colombian said living nearby and liking the course is a help.
"I'm sleeping in my own bed, I've got mom and dad here, I've got good home cooking. There's a lot of good things, a lot of good vibes around here, and maybe that has to do with my good play."
A group of 10 tied on 66 includes England's Lee Westwood, South Korean Seung-yul Noh and Americans Dustin Johnson and Boo Weekley.
Northern Ireland's Graeme McDowell and South Korea's Y.E. Yang were among another 14 players on 67.
World number one Rory McIlroy, whose victory here last year catapulted him to the top of the world rankings for the first time, carded an even-par 70, as did 14-time major champion and world number two Tiger Woods.
Both countered two bogeys with two birdies.
Woods went off the beaten track to post his par round, doffing his shoes and socks and getting his feet wet to play his half-submerged ball out of a water hazard and back to the fairway at the sixth hole, his 15th of the round.
"I wasn't trying to advance it very far," Woods said. "Just make sure I got it back in the fairway and give myself some kind of wedge shot."
Left with 81 yards to the hole, Woods hit it to eight feet and made the putt to save par.
He drained a 20-footer for birdie at the next, but for the most part didn't get hot on the greens, missing a six-footer for par at his opening hole, the 10th, and finishing with 32 putts for the round.
"I hit good putts," he said. "I was getting fooled on the grain."
McIlroy, who missed the cut in his first 2013 start at Abu Dhabi and lost in the first round of the WGC Match Play Championship last week, admitted he's still working on his timing -- and getting comfortable with his new Nike equipment.
"It's hard to commit to the shot that you need to play every time," McIlroy said. "I felt like I hit the ball OK, not as good as I can, but it's getting there."
Leading first-round scores on Thursday in the US PGA Tour $6 million Honda Classic (USA unless noted, par-70)
64 - Camilo Villegas (COL)
65 - Branden Grace (RSA), Graham DeLaet (CAN), Rickie Fowler, Robert Streb
66 - Boo Weekley, Sean O'Hair, Dustin Johnson, Fabian Gomez (ARG), Billy Horschel, Lee Westwood (ENG), Seung-yul Noh (KOR), Ben Kohles, Doug LaBelle, Brian Stuard
67 - Charles Howell, Jeff Klauk, Chris Stroud, Matt Jones (AUS), Tom Gillis, Kevin Stadler, Michael Thompson, Hank Kuehne, Jeff Overton, Brian Gay, Graeme McDowell (NIR), D.A. Points, Y.E. Yang (KOR), Patrick Reed
68 - Russell Henley, Justin Rose (ENG), Gary Woodland, Stewart Cink, Chris Kirk, Keegan Bradley, Geoff Ogilvy (AUS), Greg Chalmers (AUS), Brad Fritsch (CAN), Luke Guthrie