[26] Mickelson's first major championship win came in his thirteenth year on the PGA Tour in 2004, when he secured victory in the Masters with an 18-foot (5.5 m) birdie putt on the final hole.

The following year, Mickelson captured his second major at the PGA Championship at Baltusrol in a Monday final-round conclusion due to inclement weather the previous day.

On the 18th hole, Mickelson hit one of his trademark soft pitches from deep greenside rough to within 18 inches (460 mm) of the cup and made his birdie to finish at a 4-under-par total of 276, one shot ahead of Steve Elkington and Thomas Bjørn.

[29] This win propelled him to 2nd place in the Official World Golf Ranking (his career best), behind Woods, and ahead of Vijay Singh and Retief Goosen.

The day before his withdrawal, Mickelson said during a television interview that PGA Tour Commissioner, Tim Finchem, had not responded to advice he had given him on undisclosed issues.

[40] Mickelson's regimen consisted of increasing flexibility and power, eating five smaller meals a day, aerobic training, and carrying his own golf bag.

[42] Mickelson won his first 2009 tour event when he defended his title at the Northern Trust Open at Riviera, one stroke ahead of Steve Stricker.

Mickelson was scheduled to play the HP Byron Nelson Championship May 21–24, and to defend his title May 28–31 at the Crowne Plaza Invitational at Colonial, but withdrew from both events.

[43] During the final round of the 2009 BMW PGA Championship, fellow golfer and family friend John Daly wore bright pink trousers in support of Mickelson's wife.

On May 31, Mickelson announced that he would return to play on the PGA Tour in June at the St. Jude Classic and the U.S. Open, since he had heard from the doctors treating his wife that her cancer had been detected in an early stage.

[46] After hearing the news that his mother had been diagnosed with breast cancer, Mickelson took another leave of absence from the tour, missing The Open Championship at Turnberry.

On July 28, Mickelson announced he would return in August at the WGC-Bridgestone Invitational, the week before the PGA Championship at Hazeltine National Golf Club.

For good measure, Mickelson birdied the final hole and memorably greeted his waiting wife, Amy, with a prolonged hug and kiss.

CBS Sports announcer Jim Nantz's call of the final birdie putt, "That's a win for the family," was seen by many as capturing the moment well.

[52] Tiger Woods had a dramatic return to competitive play after a scandal-ridden 20-week absence; he was in close contention throughout for the lead and finished tied with Choi for 4th at −11.

Mickelson and others showed exciting play over the weekend, and the 2010 Masters had strong television ratings in the United States, ranking third all-time to Woods's historic wins in 1997 and 2001.

In the final round of the AT&T Pebble Beach National Pro-Am, Mickelson rallied from six shots back, winning the tournament by two strokes with a final-round score of 8-under 64 and a four-round total of 269.

Earlier in the tournament, he received widespread praise for being present to watch Jack Nicklaus, Arnold Palmer, and Gary Player hit the ceremonial opening tee-shots, nearly seven hours before Mickelson's own tee time.

However, his 25-foot birdie putt on the final hole lipped out, resulting in him missing out by a single shot on making only the sixth round of 59 in PGA Tour history.

Mickelson led the tournament wire-to-wire and completed a four-shot win over Brandt Snedeker for his 41st PGA Tour victory and 3rd Phoenix Open title.

After a missed 10-foot (3.0 m) birdie putt on 16, Mickelson hit his drive on the infamous Road Hole (17th) at the famed Old Course at St Andrews onto a second-floor balcony of the Old Course Hotel.

Later in the year, it was announced that Mickelson would leave longtime swing coach Butch Harmon, feeling as though he needed to hear a new perspective on things.

[69] After leaving Butch Harmon, Mickelson hired Andrew Getson of Grayhawk Golf Club in Scottsdale, Arizona, to serve as his new swing coach.

The next week, in San Diego, he narrowly missed an eagle putt on the 18th hole on Sunday that would have got him to 8-under par instead posting −7 (71-72-67-71) to finish T14 at the Farmers Insurance Open.

On September 6, days after posting his best finish of the season of T6 at the Dell Technologies Championship, Mickelson was named as a captain's pick for the Presidents Cup.

[80] In his third start of the 2019 calendar year, Mickelson won the AT&T Pebble Beach Pro-Am, shooting a bogey-free final round 65 to defeat Paul Casey by three strokes.

In December 2019, Mickelson announced via Twitter that "after turning down opportunities to go to the Middle East for many years" he would play in the 2020 Saudi International tournament on the European Tour and would miss Waste Management Phoenix Open for the first time since 1989.

Mickelson shot a final round 4-under-par 68 to win the inaugural Constellation Furyk & Friends over Miguel Ángel Jiménez in Jacksonville, Florida.

[88] In November 2021, Mickelson won the season-ending Charles Schwab Cup Championship in Phoenix, Arizona, with a final round six-under par 65.

In an interview, he stated that Saudis are "scary motherfuckers to get involved with... We know they killed [Washington Post reporter and U.S. resident Jamal] Khashoggi and have a horrible record on human rights.