Hoffman, who has not won on the US circuit in almost three years, barely missed a putt on the way to a flawless five-under-par 66 on a mainly overcast day at the picturesque Harbour Town Golf Links.
Wearing sunglasses, the long-haired Californian totalled only 21 putts as he posted an 11-under total of 202, ending the round two ahead of compatriot and US Open champion Webb Simpson, who fired a best-of-the-day 65.
Another American, Kevin Streelman, carded a 69 to sit alone in third at eight under, a stroke better than Zimbabwe's Brendon de Jonge (67) and Northern Irishman Graeme McDowell (68).
Hoffman, however, was the story of the day as he sank putt after putt on greens softened by overnight rain in his bid to win a first US Tour title since the 2010 Deutsche Bank Championship.
"This course was gettable today," the laidback 36-year-old told Golf Channel after a bogey-free display highlighted by five birdies. "The greens were moist and you could get after it.
"I started off good, got some good breaks and made some putts, then I sort of hung on from there on in, didn't really give myself any opportunity to make birdie. I made a lot of six-to-nine footers to save par."
Joint leader with Streelman and rookie Steve LeBrun after the second round, Hoffman made a sizzling start with four birdies in the first five holes to surge two strokes in front of the chasing pack.
Out in four-under 32, he did well to save par at the 12th after his drive sailed right into the treeline, coolly sinking a 12-footer to remain at 10 under for the tournament.
Hoffman, who had launched his round with a monster 30-foot birdie putt at the opening hole, eclipsed that at the 588-yard 15th when he rolled in a slick 38-footer to maintain a two-shot advantage.
He then made further clutch putts to save par on the last three holes, signing off with a tricky 10-footer on the 18th green to preserve his two-stroke cushion.
"I was able to leave myself underneath the hole because I was chipping all day long, so I had a lot of uphill putts," Hoffman said of his impressive putting statistics.
"If you're hitting (longer) iron shots in there, it's a little tougher because you're probably leaving yourself downhill sliders (for putts). I gave myself opportunities to make the (par) putts, and I made them today.
"I will go and work on the ball-striking now. Hopefully I will hit it a little better tomorrow and keep making the putts."
Journeyman LeBrun, at 34 playing his first season on the US Tour after spending most of his time on the satellite circuits, fell back with a run of three bogeys around the turn to end the day with a 71, five shots off the pace.
English world number six Luke Donald was a further stroke back, also after a 71.
Earlier in the day, the weather-delayed second round was completed with 91 players making the cut at two-over 144. Among those missing out were multiple Major champions Ernie Els of South Africa and Fijian Vijay Singh.
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