Hoffman had four birdies on his first five holes to shoot a bogey-free 5-under 66 and keep out front at 11 under on a windy, cool day at Harbour Town Golf Links. Simpson also didn't make a bogey on the way to a 65, tying the lowest round of the tournament.
Kevin Streelman shot a 69 and was alone in third at 8 under.
The round started with 91 players making the cut, tying the tour high set in 1981 at the Travelers Championship. Jesper Parnevik moved the cut line Saturday morning to 2 over as he missed a 5-footer to complete his rain-delayed second round and opened the door for 21 players to keep playing.
The last of Hoffman's two career PGA Tour victories came at the 2010 Deutsche Bank Championship. And early on, he threatened to turn the RBC Heritage into a runaway.
He made a 30-footer for birdie at the first to break from a three-way tie with Kevin Streelman and Steve LeBrun, then followed that by getting up and down from about 30 feet on the par-5 second hole. Hoffman was pin high, 12 feet away on the par-3 fourth to move to 9 under and closed his hot start with another up-and-down birdie -- this one from 65 feet -- on the par-5 fifth.
Hoffman played steadily the rest of the way to maintain his lead -- even though he appeared on the verge of cracking several times.
Hoffman saved par from a front bunker on the par-3 seventh hole, then punched a shot between two trees no more than 5 feet apart to make another par on the eighth hole.
Hoffman chipped to 2 feet for another par on the 11th. He rolled in a 12-foot par putt on the next hole to stay out front during Simpson's charge.
Hoffman's final birdie -- on the par-5 15th -- gave him the two-stroke edge. He made a testy, 12-footer to save par one last time at the famed lighthouse hole, No. 18.
Simpson started three shots out of the lead, birdied three of his first six holes. Two more birdies on the 10th and 11th holes moved him within two shots of Hoffman. Simpson's 15-foot birdie putt on the 15th -- Simpson made birdie on all three of Harbour Town's par 5s -- drew him closer still. Simpson's 65 matched the lowest round of the tournament, accomplished Thursday by opening-round leader Brian Davis.
Streelman, tied with Hoffman and rookie LeBrun through 36-holes, had consecutive birdies on the 13th and 14th holes to stay in contention. LeBrun held steady with a 71 and was in a group of eight five strokes behind that included Bill Haas.
Hoffman's steady play capped an odd Saturday at Harbour Town that featured an early start time to conclude round two, a super-sized field of competitors and a quick turnaround to get the third round in.
Parnevik was about to putt out on the closing lighthouse hole Friday evening when the horn sounded, stopping all play. Soon after his missed putt Saturday morning, Parnevik joked on Twitter, "Everybody in the field at plus-2, put your envelopes in my locker ..."
One of those was Brandt Snedeker, at No. 5 in the world the highest ranked golfer here and on the verge of missing the weekend after shooting 73-71. Snedeker, who contended for the Masters' title last Sunday, was not spectacular in his bonus round, but did enough with an even-par 71 to hang around Sunday.
One of those who didn't make the tournament's second cut was Parnevik after a 73.
The tournament sent players out in groups of three on the first and 10th tees and that briefly created a backlog -- and a scene duplicated at nearly every public course in the country -- when the early starters on one side met the late starters on the other. Bo Van Pelt munched on a sandwich as he waited on No. 10 for the final competitors, Nicolas Colsaerts and Casey Wittenberg, to tee off before his group could continue.
DIVOTS: The final round will have 70 players at 2 over par or better -- which would've been the number Saturday if not for Parnevik's miss. ... The PGA Tour's records on the cut only go back to 1970, so it's unknown if a tournament before then ever had more than the 91 players at the RBC Heritage make it past a 36-hole cut. ... Former Masters champ Trevor Immelman needed Parnevik's miss to play the third round, then shot a 5-under 66 to move to 3 under. ... James Driscoll had two birdies Saturday and nine for the week, good for a $9,000 donation for One Fund Boston. The Massachusetts native has pledged $1,000 per birdie he makes at the RBC Heritage and the Zurich Classic of New Orleans go to victims of the Boston Marathon bombings. He missed the cut after third-round play.