Mickelson began the day with a one-stroke lead but despite a sensational eagle-two at the par-four 10th when he holed out from the rough, the big left-hander finished two shots behind winner Justin Rose to finish runner-up once again.
In tying Australian Jason Day after shooting a final-round 74 for a three-over-par 284 total, Mickelson extended his US Open record with a sixth second-place finish.
"For me it's very heartbreaking," Mickelson said. "This could have been a really big turnaround for me on how I look at the US Open, the tournament that I'd like to win, after having so many good opportunities."
Mickelson had finished second best in 2009, 2006, 2004, 2002 and 1999, but the big left-hander thought he was poised to finally break through at Merion after being in the lead after each of the first three rounds.
"I think this was my best chance," said Mickelson, who bogeyed three of his last six holes to yield the advantage to Rose. "The way that I was playing heading in, the position I was in and the way I love the golf course."
Mickelson gave himself a slew of birdie opportunities but burned the edges with numerous putts and failed to execute with his vaunted short game down the closing stretch.
Regarded as one of the game's best wedge players, Mickelson misfired at the 13th and 15th holes leading to bogeys.
At 13, he fired a wedge shot too strong, directly over the flag into thick tangly rough behind the green.
Two holes later he landed a gap wedge shot too short and it trundled back off the green leading to another bogey.
"Thirteen and 15 were the two bad shots of the day that I'll look back on where I let it go," he said.
Mickelson said he felt his putting stroke was in fine order though he had little to show for it.
"The stroke felt fabulous all day, starting at the first hole. I can't believe that ball didn't go in," he said. "Second hole I hit a good putt. It was really rough around that hole there.
"I hit a good putt for eagle on four. Hit a good putt on six. I thought I made that. I thought I made the one on eight. Thought I made the one on nine.
"I thought I had a chance on 12. Certainly 16, I thought I made."
Mickelson said of all his Open near misses, this one hurt the most.
"This one's probably the toughest for me, because at 43 and coming so close five times, it would have changed the way I look at this tournament altogether and the way I would have looked at my record. (Instead) I just keep feeling heartbreak."
- Sports & Recreation