And while the crushing nature of that defeat didn't hold Mickelson back -- he went on to win two more majors -- the memories from Winged Foot will no doubt forever stick with him.
While that career grand slam still remains elusive to Mickelson as he returns to Winged Foot for the 120th US Open Championship, which begins on Thursday, one thing that has changed is his body. He took to Twitter to show his transformation since 2006, admitting he looks a little "different" now.
"Last time I was at Winged Foot, I was 36 years old with no accountability for my health ... After becoming accountable for my own health, today I return to Winged Foot and let's just say I look a little 'different.'"
When Mickelson lost that heartbreaker at Winged Foot 14 years ago, the winning score was five over par. The score to make the cut that year was 13 over.
In contrast to the 13 under Gary Woodland shot in June last year to win the US Open at Pebble Beach, many are expecting another over-par score to win the championship in 2020.
"If it gets firm like some of the USGA guys (the tournament organizers) told me they want it to be, I don't see how any of us shoot under par. Or if we shoot under par, it would be somebody winning by a lot."
In 10 PGA Tour events, the 36-year-old has won three and finished second twice -- including last month's PGA Championship -- and also won the season-ending FedEx Cup title.
Entering the US Open, Johnson is undeniably the man to beat, and he told the media that he was "pleased" with the way his game has been "clicking" in recent competitions.
"I've spent a lot of time with (coach) Claude (Harmon III) and my brother working on the putting and everything just seems to be clicking right now. But I've definitely had to put in a lot of work to get to where I'm at. And obviously the game's good and it feels good."
"When I didn't win the Masters that year, that was really tough to take because that was the last event my dad was ever going to watch me play.
"He passed not too long after that, and quite frankly, when I got ready for this event, I didn't really put in the time. I didn't really put in the practice, and consequently missed the cut pretty easily."
Now the 44-year-old is back at Winged Foot hoping to create new, more positive memories as he aims to win his first US Open title since 2008.
Since golf returned from the break, Woods has struggled for fitness and form, playing in just four PGA Tour events, his highest finish coming at the PGA Championship when he tied for 37th.
"This year I really haven't putted as well as I wanted to," Woods said, "and the times I did make a few swing mistakes, I missed it in the wrong spots. Consequently, I just didn't have the right looks at it. I've compounded mistakes here and there that ended up not making me able to make pars or a birdie run, and consequently I haven't put myself in contention to win events."