Villegas soared to the top of the leaderboard with an eight-under-par 63 at Riviera Country Club as Spieth spluttered to a 79 that included eight bogeys and a double on his final hole.
"I've shot in the 80s a couple times on Tour," Spieth told reporters after carding his worst opening round on the PGA Tour. "In the course of a career, I imagine it's going to happen. Just unfortunate when it actually does.
"I just played really poorly from good positions off the tee and didn't strike the iron shots bad either," added Spieth, who tied for fourth last year. "I just overdrew it when you can't be left and I overcut it when you can't be right. Just bad timing."
The Masters and U.S. Open winner said he had struggled adapting to a Riviera layout that had run firm and fast earlier in the week before being softened by overnight rain.
"I found it very difficult to trust the way the golf course is playing," explained the 22-year-old, who missed putts from eight and then four feet to run up his double bogey at the par-four 18th. "I've never played the golf course soft."
While Spieth sunk like a stone to near the bottom of the leaderboard, Villegas seized control with a storming back nine highlighted by four consecutive birdies before he ran up his only bogey of the day on his final hole.
"Things were going good there," said Villegas, a four-times winner on the PGA Tour whose most recent victory came at the 2014 Wyndham Championship. "Obviously the rain yesterday made the golf course a lot more accessible.
"It was pretty stress-free today. I hit the ball good, I kept it in play. I didn't put myself in tough positions on a golf course where you can put yourself in tough positions, and here we are, nice little 63 to get started."
The Colombian's nine-birdie round left him three strokes clear of 2014 champion Bubba Watson, Chez Reavie and Luke List.
World number three Rory McIlroy, making his first PGA Tour start of the year, was a further stroke back with six other players after opening with a 67.
"I felt for the most part I played well," said McIlroy, a four-times major champion. "I felt like my pace on the greens was good ... and I lag-putted well. All of the things that you need to do around this golf course, I did pretty well today."
Play was suspended for the day in fading light with 14 players still out on the course, South African Tyrone Van Aswegen the best placed at four under with two holes to complete.
(Editing by Frank Pingue/Peter Rutherford)
