Villegas carded a flawless seven-under-par 63 to take the lead into the clubhouse and then watched the rest of the field falter, making him the first South American to win the event.
The 32-year-old Colombian made his move early, storming around the front nine in 29 strokes, which included a five-foot eagle at the par-five fifth at Sedgefield.
"I'm pretty hard on myself. I've always worked hard and believed in myself, sometimes more than others, and I'm happy to be here," Villegas told reporters after holding his nerve with a steady back nine to clinch his fourth PGA Tour victory.
Villegas finished at 17-under 263 to edge Swede Freddie Jacobson (66), who bogeyed the last after missing a 10-foot putt, and American Bill Haas (64).
"It really sucks when you play solid all day," Jacobson said. "I really thought it was my day coming in."
He was not the only one to squander a chance of winning the event previously known as the Greater Greensboro Open.
Third round leader Nick Watney led with seven holes to play but closed poorly, running up a double-bogey at the last after slicing his tee shot out of bounds.
"That was a really bad shot at a really bad time," five-times PGA Tour winner Watney lamented after carding 70 to tie for fifth on 14-under.
Fellow American Heath Slocum also shared the lead with two holes left, but finished bogey-bogey to fall back to fourth at 15-under.
It may not have been the most exciting way for Villegas to secure victory, sitting in air conditioned comfort watching his rivals falter, but he was not fussy after enduring a four-year title drought and falling to 254th in the world rankings.
"I was hoping for a playoff. Even though I played great today I thought I needed one more (birdie)," he said as he sat beside the Sam Snead Cup, named for the eight-times Greensboro winner.
Villegas said his apparent slump over the past couple of years was not as bad as it seemed looking at results.
"There's such a small margin between playing good, playing average, playing bad," he said. "We choose a pretty interesting game to make it our job and you've got to be patient. I've been learning that maybe taking it a little bit easier on myself is a good equation."
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