Mickelson ended the tournament at 19-under-par 269 and became the first player to win this event in its 72-hole format in wire-to-wire fashion. He won for the second straight week for the first time in his career.
'It's been fun. I've played well the last couple of weeks,' said Mickelson after winning for the 25th time on the PGA Tour. 'I'm very excited to get the year off with a couple of wins. It sure feels good.'
Weir, the 2003 Masters champion, posted the round of the day as he closed the event with a 5-under 67 to finish at 15-under-par 273. Englishman Greg Owen took third place at minus-13 after a closing 72.
Tim Clark and Paul Goydos carded matching rounds of 1-under 71 to end the tournament at 12-under-par 276.
Mickelson began the week with a stellar 62 to establish a new course record at Spyglass Hill. He went on to set new 36- and 54-hole scoring records before finishing one off the tournament scoring mark owned by Mark O'Meara.
He got his final round going at Pebble Beach with a birdie from 3 feet out at the par-4 fourth to climb to minus-21. At that point, Mickelson led by nine strokes.
Mickelson stumbled to a bogey at the par-5 sixth and another at the ninth. The reigning Masters champion slid back to minus-18 when his par putt at the 10th rolled by the left edge.
His lead had fallen to four shots over Weir, but Mickelson was undaunted. He came right back to sink a 20-foot birdie putt at the 11th to get to 19 under.
From there, Mickelson battled to seven straight pars to close his round. From the 12th to the 16th, Lefty missed makeable birdie putts on each green, then converted an excellent up-and-down par at 16. He two-putted for par on each of the final two greens to close out the win.
'I was trying to get through the first 10 holes without making a big mistake,' said Mickelson. 'The first 10 holes were mostly into the wind. I thought I could make birdies coming in because the wind was starting to help.'
Mickelson was not deterred all week by the slow pace of play. He actually tried to relish his time on the course despite the fact that his final round took just under six hours.
'You have to accept the fact that they're going to be long, long days and relish it,' Mickelson said. 'When you get great partners to play with, you are able to enjoy the day and six-hour rounds don't seem like six-hour rounds.'
Weir, who has come from behind in six of his seven wins, started the day 10 shots behind Mickelson. The Canadian got off to a hot start as he drained birdies at one and two to get to 12 under.
Weir tripped to a bogey at the third, but erased that mistake with a birdie at No. 4. He picked up birdies at nine and 11 to get within four.
However, he ran off six consecutive pars from the 12th. Weir birdied the par-5 18th to secure second place.
'I played one of the better rounds I've ever played,' said Weir. 'It could have been a really special round if a few things could have dropped for me.'
Darren Clarke and Arron Oberholser each closed with 71s to share sixth place at 11-under-par 277. Graeme McDowell also posted a final-round 71 to end at minus-10.
Davis Love III, the 2001 and 2003 champion here, finished in a tie for ninth at 9-under-par 279. He was joined there by 1992 runner-up Jeff Sluman.
Joel Kribel (70), Billy Andrade (73), Luke Donald (71), Robert Gamez (73) and Charles Howell III (72) shared 11th place at 8-under-par 280. Kribel and his amateur partner, Barry McCollam, were the winners of the Pro-Am portion of the tournament.