The American lefthander, chasing a record-equalling fifth victory in the pro-am event held on the picturesque Monterey Peninsula, fired a flawless six-under-par 66 on the Pebble Beach host course, one of three venues being used for this event.
Mickelson broke clear of a congested leaderboard with three consecutive birdies on his back nine on the way to a 16-under total of 199, two ahead of Japan's Hiroshi Iwata, who carded a 69 at Spyglass Hill.
Swede Freddie Jacobson, after a 68 at Monterey Peninsula Country Club, and South Korean Kang Sung-hoon, who returned a 70 at Pebble Beach, were a further stroke back at 13 under.
“I fought hard today,” the 45-year-old Mickelson told Golf Channel. “The golf course was playing much more difficult with the firm greens and the wind picking up.
“There were a lot of holes I just had to fight for pars. I probably didn't strike it as well as I have been striking it this year, or even in the first couple of rounds.
“But I was able to get up and down, miss it in the right spot and salvage a lot pars on some difficult holes today.”
An early morning fog delay gave way to unbroken sunshine at Pebble Beach before Iwata, Jacobson, England's Justin Rose and Kang held a share of the lead at 13 under midway through the round.
Mickelson then made it a five-way tie at the top when he chipped in for birdie from just off the back of the green at the par-five 18th, his ninth hole of the day.
The American seized control after the turn, his run of three birdies from the fifth putting him two ahead of the chasing pack before he safely parred the eighth and ninth to remain on course for his first PGA Tour win since the 2013 British Open.
“It really does feel good to finally get the scores out of it, to know that I am playing well,” said Mickelson, who is aiming to equal Mark O'Meara's record five wins at Pebble Beach.
“I know that, as I look back on those other victories here, how special they were ... I've got a little bit of work to get my ball striking back to that level that I need it to be for tomorrow's round. But it's fun to be back in the thick of it.”
World number one Jordan Spieth again struggled with the pace of the greens as he carded a 74 at Pebble Beach for a one-under total, making the cut right on the number.
Original source: Mickelson eyes end to title drought