Mickelson began his round with two birdies and, after making the turn at four-under par, enjoyed back-to-back birdies on the 14th and 15th to sign for a five-under 67.
That was enough to move him clear as those who had shared a seven-way tie for first after the opening round struggled to maintain their form on Friday.
Nick Watney did the best of them with a round of 70 - three shots worse off than his opening effort - to join a three-way tie for second along with Scott Gardiner and George McNeill, while Rory McIlroy was in a five-way share of fifth, three shots off the leader.
McIlroy, tackling the back nine of the course first, briefly found himself atop the leaderboard but he would have two bogeys before making the turn.
He salvaged his round with three birdies on the way back home to sign for a 71.
The world number two admitted he struggled with his putting before finding a feel for the course.
"The greens were a lot faster today [Friday] than they happened to be yesterday [Thursday] afternoon," McIlroy said on PGATour.com. "It took a little bit of time to get adjusted.
"But I think this week it's all about fairways and greens. If you can do that, not every putt's going to drop, but I think if you've given yourself the chances, you take a few of them and you'll be right there."
Rod Pampling, Jason Kokrak, Derek Ernst and Lee Westwood joined him at six under, with Westwood in fine form despite battling a chest infection as he carded a 68 to move up from joint 18th.
His day could have been even better but for bogeys on the seventh and 12th holes.
It was his best round here in his last five attempts, and Westwood concluded he had earned some rest after a tough day under the weather.
"I just won't do too much practice this afternoon [Friday]," he said. "I'll just go back to the room and lie down, really."
Daniel Summerhays and Nate Smith, who both surrendered leads late in their opening rounds, fell off the pace with disappointing second days.
Summerhays slipped to joint 13th after a round of 73, while Smith was one shot worse off in joint 21st.