The five-times major winner moved in front with another birdie at 14 and added his sixth birdie of the day at the 17th to shoot a bogey-free six-under 66 on the PGA West Stadium Course at La Quinta Country Club for a 22-under 194 total.
"I gave myself a lot of good chances," Mickelson told Golf Channel. "I missed a few short putts that I have been making historically now for a while and I let a few slide.
"But I also made a couple of long ones that were bonuses."
A 35-footer at the sixth hole marked the start of three consecutive birdies on the front nine for Mickelson, who also made a 36-footer at 17 to maintain the two-stroke advantage he started the day with.
A win would give Mickelson, who shot a 60 in his opening round, the 44th title on the PGA Tour.
Hadwin, playing the Nicklaus Tournament Course, put together seven birdies for his bogey-free round of 65 to finish at 20-under 196.
"I was playing one of the easier golf courses so I knew I had to keep the pedal down," the Canadian told PGA Tour Radio. "Again a kind of slowish start but I kind of caught fire midway."
He collected three birdies on the front nine, then added four more in six holes after the turn.
He shot 59 at La Quinta in 2017 but has never won a tournament there.
Adam Long, with a sizzling nine-under 63, was a stroke behind Hadwin on 19-under, with fellow American Steve Marino (67) at 18-under.
Australian Curtis Luck, who had been two strokes off Mickelson's second-round lead, faded with a four-over 76 that left him 12 shots off the lead.
(Reporting by Gene Cherry in Raleigh, North Carolina; Editing by Peter Rutherford)
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