The Open champion, fourth in the FedEx Cup standings, was on course to card a magical 59 after opening his round on the back nine with seven birdies to reach the turn on 28.
While the left-hander, who opened with a round of 60 at the Phoenix Open earlier this year, bogeyed the first, he then eagled the next after landing his second shot to two feet from the pin. However, a run of pars followed before the American finished birdie-bogey at TPC in Boston.
It was still enough for a one-shot clubhouse lead over compatriot Kevin Stadler, who made eight birdies and one bogey in his round of 64.
World No 1 Tiger Woods and Masters champion Adam Scott were in the same playing group as Mickelson. Woods struck a 68 but Scott was off the pace after a two-over-par round.
Hunter Mahan is currently just behind countrymen Mickelson and Stadler after a six-under-par round, while England’s Lee Westwood is in a group of nine players one shot further back.