Mickelson held his nerve during a pulsating final round at Kiawah Island to win his sixth major title in the 103rd US PGA Championship, 16 years on from lifting the Wanamaker Trophy for the first time.
The 50-year-old carded a closing 73 amid euphoric scenes around the 18th green, finishing six under par and two shots ahead of Brooks Koepka and Louis Oosthuizen, with Shane Lowry, Padraig Harrington, Paul Casey and Harry Higgs two strokes further back.
A 280-1 outsider at the start of the week, Mickelson will celebrate his 51st birthday on June 16, the day before the US Open – which he needs to win to complete the career grand slam – gets under way at Torrey Pines.
Julius Boros had been the previous oldest major champion, claiming the US PGA title in 1968 at the age of 48.
Mickelson took a slender lead over Koepka into the final round but there was immediately a two-shot swing, Mickelson three-putting the first from long range and Koepka holing from 12 feet for birdie.
But that was eclipsed minutes later as Mickelson got up and down from over the third green for a birdie and Koepka missed the green with his approach, duffed his fourth shot from a sandy waste area and eventually two-putted for a double-bogey seven.
Another two-shot swing looked certain on the third after Mickelson made bogey with Koepka in close, but the former world number one surprisingly missed from two feet.
Mickelson rubbed salt into the wound on the par-three fifth, holing out from a bunker for birdie after Koepka had hit a superb tee shot to 25 feet, but Koepka responded with a tap-in birdie on the next as Mickelson failed to save par from right of the green.
The tie for the lead did not last long however, yet another two-shot swing coming on the par-five seventh thanks to a Mickelson birdie and clumsy Koepka bogey.
Pars from both players on the eighth and ninth came as something of a welcome chance to pause for breath, but the lull in action was short-lived.
Mickelson's birdie on the 10th and a bogey from Koepka was the fifth multiple-shot swing between the final pair and gave Mickelson a four-shot lead with eight holes to play.
With Koepka's challenge crumbling rapidly after another dropped shot on the par-five 11th, Oosthuizen took up the chase thanks to a timely birdie on the 12th, only to promptly dump his third shot to the next into the water and run up a double bogey.
If Mickelson was aware of the situation he certainly did not act like it, taking on the flag on the same hole and also finding the water, but a favourable drop allowed him to limit the damage to a single shot.
The gap was down to three when Mickelson also dropped a shot on the 14th and contracted even further as Oosthuizen birdied the 16th, agonisingly missing from 15 feet for eagle.
Koepka had also kept his hopes alive with a birdie on the 15th and hit a thunderous drive of 361 yards on the par-five 16th, only to see Mickelson amazingly hit his five yards further.
Both men made birdie and Mickelson was happy to play conservatively for a bogey on the 17th after his tee shot ran through the green into thick rye grass.
Mickelson was almost mobbed by spectators after hitting a superb approach to the 18th and needed assistance from security guards to force his way on to the green.
Koepka could not find a birdie to at least increase the pressure and the stage was left clear for Mickelson to two-putt for par and complete an extraordinary victory.
Open champion Lowry and Ryder Cup captain Harrington had set the early clubhouse target, the good friends playing together and carding matching rounds of 69.
"I went away from the Masters like this, and just a little bit more so this week, feeling 'What if?'" said Lowry, who finished 21st at Augusta National last month.
"But that's a great feeling to have, feeling like I was close to having a great chance this week.
"When Paddy chipped in on 14, I was like, 'Ooh, Paddy has got a chance here'. I was kind of trying to cheer him on and play my own game, but honestly playing with Paddy today was one of the best rounds of golf I've ever had. It was so much fun."