American Simpson, who teed off at the par-four 10th hole, had only one bogey on his way to an eight-under-par 63 at the TPC Summerlin in the second event of the PGA Tour's 2013-14 season.
The North Carolina native, who won last year's U.S. Open at Olympic Club in San Francisco, birdied five of his last nine holes to post a 15-under total of 127.
Simpson led by four strokes from fellow Americans Jeff Overton (68) and Chesson Hadley (66) and Australian John Senden (68) with half the field back in the clubhouse.
"The ball was really going far," Simpson, 28, told Golf Channel after hitting 15 of 18 greens in regulation and needing only 24 putts.
"I was wondering why scores were so low yesterday but the course played a little shorter than I thought it would.
"I just putted well and kept it going. I think guys are going to keep making birdies so I've got to keep the hammer down."
The TPC Summerlin regularly yields low scores in the high Nevada desert where fine weather, thin air and smooth greens usually lead to birdies galore. American Ryan Moore won last year's title with a 24-under total.
Simpson finished on a high note with a birdie on his final hole, the par-five ninth, despite a poor drive that forced him to lay up, before he struck a nice approach shot to nine feet.
Earlier, he rolled in a 25-footer at the par-four sixth, after hitting it to inside 10 feet at the previous hole.
Simpson's 63 was the best score among the early starters, but he was not the only player to go low. Compatriot Luke Guthrie shot a 64 to trail by six strokes while several others carded 65s.
World number 24 Simpson is the second-highest ranked player in the Las Vegas field.
Though he has not won since his US Open breakthrough, he has been in consistent form. He has not missed a cut since early June and is coming off a fourth-place finish at the 2013 season-ending Tour Championship.
Simpson also played on the victorious US team at the Presidents Cup earlier this month.
American J.J. Henry, who held a one-stroke lead overnight after opening with a sizzling 11-under-par 60, was among the late starters on Friday.