The big lefthander made everything from inside 10 feet on the soft greens, making him 31-for-31 from those distances during the first 36 holes for a nine-under total of 135.
Tied for second on 137 were fellow Americans Nick Watney (70) and George McNeil (68), and Australian Scott Gardiner (67), who made four birdies in a row from the sixth in bouncing back after missing his last eight cuts on the US Tour.
Another stroke away was a group that included world number two Rory McIlroy (71) of Northern Ireland, Englishman Lee Westwood, who shot a 68 despite feeling under the weather with a chest infection, and Australian Rod Pampling (69), the 10th and last alternate to join the field.
Mickelson, who considers the course one of his favourites and has finished 12th or better seven times in nine appearances, took advantage of greens softened by rain and cool temperatures, including two putting surfaces resodded just seven days ago.
"They're slower so we can be more aggressive, and I've made a concerted effort to give myself uphill putts which allows me to take a lot of the break out and be aggressive," Mickelson said after the round.
"On this course they have a lot of holes that are repelling, where if you miss it just a little bit it will kick the ball away. When the greens are firm and fast you have to respect that and play about 20 or 30 feet away. But with the greens softer we're able to fly it at the hole and stop it."
McIlroy, looking for his first win this season after switching his ball and clubs this year, shared in a seven-way tie for the overnight lead after a first-round 67 but fell back after a one-under 71 on Friday.
"The greens were a lot faster today than they happened to be yesterday afternoon," said McIlroy, who started in the morning wave. "It took a little bit of time to get adjusted. But I think this week it's all about fairways and greens.
"If you've given yourself the chances, you take a few of them and you'll be right there," he added after hitting 15 greens in regulation.
Mickelson praised the layout, which will host the 2017 US PGA Championship, and said it would mean a lot to him to carry on to victory.
"I think from tee to green it's one of the best we have, one of the best I've ever seen in the game," said Mickelson, who hit only five of 14 fairways but rescued himself with fine recovery shots, and chips and sand shots from around the green.
Mickelson ranked a lowly 130th in the field in driving accuracy and just 103rd in hitting greens in regulation.
"It's a tournament I've had many opportunities, a lot of great chances to win," he said. "I've had great finishes here but I haven't capped it off. I enjoy playing here so much that it would mean a lot to win.
- Sports & Recreation
- Rory McIlroy