Davis Love III, Kevin Sutherland, Daniel Chopra, Hunter Mahan and Charles Howell III share second place at 7-under-par 65.
Spyglass Hill Golf Course is one of three courses in rotation this week along with Pebble Beach Golf Links and Poppy Hills Golf Course, with Pebble Beach serving as the site of the final round.
Mickelson, coming off his first win of the season at the FBR Open last week, where he shot a 60 in the second round, had no problems with Spyglass Hill, historically the most difficult of the three layouts, and jumped out of the gate with birdies on each of the first two holes.
'I've really enjoyed playing the last few weeks and I can see the improvement,' said Mickelson, who won this event in 1998. 'It's just been a lot of fun.'
The reigning Masters champion birdied two in a row from the fourth and added back-to-back birdies starting at the par-5 seventh to go out in 30.
Mickelson continued the birdie barrage at the par-5 11th and knocked his second shot within 25 feet at the par-5 13th. He two-putted for another birdie and pitched his approach inside 3 feet for a birdie at the par-4 17th.
At the par-4 18th, Mickelson played his second shot to 14 feet and drained the birdie putt to complete a sizzling first round.
'The goal is to play well tomorrow at Poppy Hills and try to shoot low again,' said Mickelson. 'I've been hitting some good drives. The distance has really helped.'
Love, a two-time winner of this event, took on Poppy Hills and quickly birdied the 10th, his first. He tallied back-to-back birdies from the 12th and collected birdies at the 15th and 18th to make the turn at 5 under.
He stumbled to a bogey at the third but countered with a birdie at the par-3 sixth. Love then eagled the par-5 ninth to join the group in second place.
Howell played Pebble Beach on Thursday and got his round going with three consecutive birdies starting at the par-4 fourth. He then birdied the 11th and picked up another birdie at the par-5 14th.
The 25-year-old dropped his second shot inside 8 feet for a birdie at the par-4 15th and finished off his round with a birdie at the par-5 18th to finish three shots behind Mickelson.
Mahan birdied four of his last six holes at Pebble Beach for his 65 while Sutherland mixed nine birdies with two bogeys at Poppy Hills. Chopra played Pebble Beach and birdied the par-5 18th for his piece of second.
Mike Weir joined Dicky Pride and Mario Tiziani in a tie for seventh place at 6-under-par 66.
K.J. Choi was one shot further back at 5-under-par 67 along with Todd Hamilton, Andrew Magee, Greg Owen, Ted Purdy, Tim Clark and Paul Goydos.
Defending champion Vijay Singh, who kicked off his stellar 2004 campaign with a victory at this event, had a difficult first round of 73 at Spyglass that included a triple bogey at the par-5 seventh.