Mickelson's 63 matched that of Tiger Woods in 1998, Duffy Waldorf in 1999 and Ben Crane in 2003 as the lowest rounds on the TPC at Sugarloaf.
Gavin Coles, a two-time winner on the Nationwide Tour, posted an 8-under-par 64 to take second place. Charles Warren, who owns three Nationwide Tour crowns, is one stroke further back at minus-7.
Mickelson came flying out of the gate with a birdie on the first. He came right back with a 3-foot birdie putt on the second.
The 35-year-old parred the third, but kept rolling with a two-putt birdie on the fourth. Mickelson hit a wedge to 5 feet at the fifth, and made that to get to 4 under through five holes.
Mickelson got up and down for birdie from over the green on the par-5 sixth. He dropped a pitching-wedge within 3 feet at the seventh to setup his sixth birdie.
The 2004 Masters champion faltered to a three-putt bogey on No. 8 to slip to 5 under.
'I hit a good putt, overplayed it and I should have known from watching another ball not break as much,' said Mickelson of his bogey. 'I just didn't pay attention and played three inches outside left edge, which was too much, but no complaints.'
Around the turn, Mickelson ran home a lengthy birdie putt to get back to 6 under. The former Arizona State star stuck a wedge 3 feet from the cup on 14 and dropped in that putt for another birdie. Mickelson's tee shot at the par-3 16th stopped 6 feet from the hole and he poured in that birdie putt.
Mickelson's approach shot at the 17th came to rest just over 25 feet from the hole. He drained the birdie putt, then missed a birdie at the last that would have given him the course record.
'Any round could have been better, but it could have been not nearly as good, either,' Mickelson said. 'I had a lot of putts that went in. I'll absolutely take it. I'm ecstatic with how it turned out. I hit a lot of good shots, but I also followed it with some good putts, and it was a good day overall.'
Coles was the early leader before Mickelson hit the course. Coles played the back nine first and picked up birdies on Nos. 10, 13 and 15. Then at the par-4 17th, he holed a 5-iron from 190 yards out for eagle.
The Australian came right back with a birdie on the par-5 18th to make the turn at minus-6. Coles made it two straight as he birdied the first around the turn.
Coles got to eight-under with a birdie on the par-4 fifth. He tripped to his only bogey on the seventh. Coles quickly atoned for that error with a birdie on the eighth. He closed with a par on No. 9
'I've been working hard with my coach, really hard,' Coles said. 'He's been over in the States working with Rodney Pampling obviously at Bay Hill, and I got to squeeze in a little time with him. I played last week, but didn't play very good until about the last five holes where I started to play quite nicely. My swing is getting better all the time.'
David Howell, who won the HSBC Champions Tournament on the European Tour in November, carded a 5-under-par 67. He shares seventh place with Brett Wetterich.
Luke Donald and Padraig Harrington each shot 68. They were joined in ninth place at minus-4 by Mark Wilson, Shane Bertsch, Matt Kuchar, Stephen Leaney, Boyd Summerhays and Danny Ellis.