Mickelson started early on the 10th tee and went a sizzling seven-under through his opening nine holes as he quickly showed how easy scoring could be on the soft greens at the TPC Boston before closing with an eight-under par 63.
"I played really well, obviously putted really well," said Mickelson, who admitted that at the turn he had considered his chances of shooting just the sixth 59 on the US PGA Tour.
"The greens were perfect on my front nine and I saw the line and just rolled them in. It felt really good to putt like that."
But with the shadows falling, England's Brian Davis, bogey-free throughout his round, drained a curling 25-foot putt on his final hole to finish with two consecutive birdies and earn his place atop the overnight leaderboard.
Open champion Mickelson's hopes of a truly remarkable score were undone by bogeys on the first and last holes of his back nine, although an eagle at the par-five second ensured he did not undo much of his outstanding start.
Mickelson, the world number three, was grouped with Tiger Woods and Adam Scott, ranked first and second in the world, respectively, and he set the perfect tone with a 19-foot putt for birdie on his opening hole.
The left-hander birdied every hole on the back nine except the par-four 12th and 13th, producing pin-point iron shots and composed putting.
But Mickelson's round could easily have unravelled on his final hole, the par-four ninth, where he drove far right into the trees and clambered into the woods where he characteristically managed to blast the ball out to the rough.
From there, the American found the green and two putted for a bogey.
Woods, the FedExCup points leader, mixed four birdies with a bogey for a three-under 68 while Australian Scott (73) had three bogeys and a lone birdie on an ideal morning for low scoring.
"It was a decent day, I didn't hit the ball as well as I'd like to but I scored all right. Missed a few opportunities," said Woods, who showed no indications of his recent back troubles. "The back was fine, all good."
Davis, who came into the tournament ranked 71st in the FedExCup standings, was delighted with a flawless display.
"I played great, from tee-to-green it was good. Got up and down a couple of times and putted really solid today. I didn't make any mistakes and shot a great round. I'm delighted," said the 39-year-old Englishman.
American Kevin Stadler (64) was a shot behind the leaders while compatriots Hunter Mahan and Roberto Castro and Spain's Sergio Garcia were a further shot back after carding 65s.
Garcia got on a roll on the front nine, his back nine, with four consecutive birdies from the second hole.
"I think it's the kind of course that you can score if you're striking the ball well," said the Spaniard. "If you drive the ball well you can attack a lot of these pins. If you struggle in fairways it can be quite tricky.
"With good weather that we're going to have it's going to get firmer as the week goes on. Today the greens were a little bit softer, so it was easier to attack them," he said.
Defending Deutsche Bank champion Rory McIlroy and 2013 US Open winner Justin Rose both shot one-under rounds of 70.