Stanislas Wawrinka reached his first Grand Slam semi-final by stunning the reigning Olympic and Wimbledon champion, booking a Saturday last-four date against either world number one Novak Djokovic or Russian 21st seed Mikhail Youzhny.
Spanish second seed Rafael Nadal and French eighth seed Richard Gasquet will meet in Saturday's other semi-final.
"It feels amazing for sure, especially after that match against the defending champion," Wawrinka said. "It was a crazy match for me to beat him in three sets."
Relentless pressure from Wawrinka, who is deeper than 17-time Grand Slam champion compatriot Roger Federer in a Slam for the first time in his career, led to a Murray meltdown that doomed his repeat dreams.
"He played great. That was the hardest part about the match," Murray said.
"He just hit the ball extremely well. I didn't create a break point chance. He served well. He hit a lot of lines, was going for big shots, and he played too well."
A grim-faced Murray set a record for hustling to the interview room, arriving before Wawrinka could even leave the court after the match, the 26-year-old Scotsman's stoic visage a sign of his unhappiness.
"I would have liked to have played a little bit better," Murray said. "It's a shame I had to play a bad match today."
For only the second time in 146 Grand Slam matches, Murray failed to manage even a break point against an opponent, and it came on a day when Wawrinka ignored the wind to fire 45 winners, three times Murray's total.
"The first set was not really easy. It was very windy. We were trying to find the game," Wawrinka said. "To get that gave me a little bit of confidence for sure.
"I was trying to focus on what I did, playing solid and aggressive, to go for taking the match and not let him come back."
The 28-year-old Swiss lost in the quarter-finals of three prior Slams, including this year at the French Open, but became only the third man from his nation to reach a Slam final four, joining Federer and Marc Rosset.
Murray had won eight of 13 prior matches with Wawrinka, but his defeats included a third-round loss at the 2010 US Open.
Murray saved the first five break points of the match in the 10th game of the first set, errant backhands by the Swiss standout helping his cause.
But Murray swatted a forehand long on Wawrinka's sixth break chance to drop the set, smashing his racquet on the court a moment later in frustration.
"That 5-4 game in the first set was important game," Murray said. "I had a chance to close it out. He had quite a few chances. I made a few mistakes."
Murray saved a break point in the second game of the second set and held in the fourth, but after losing the first point of the sixth set he screamed at himself, "I'm serving like a donkey."
After netting a backhand two points later, Murray was down triple break point and Wawrinka broke him at love with a backhand winner, then held at love to 5-2, capping a run of 12 points in a row, and again to claim the second set.
Murray, with seven career comebacks from two sets down, screamed as he sat down after the set, staring at the court, talking to himself and shaking his head as music blared from the stadium loudspeakers.
He double-faulted away a break to hand Wawrinka a 2-1 lead in the third set and the Swiss ripped a forehand winner -- his 42nd of the match -- past Murray for a break and a 5-2 lead on the way to victory after two hours and 15 minutes.
Wawrinka is only 2-12 against Djokovic, including fourth-round losses at last year's US Open and this year's Australian Open, and 2-3 against Youzhny, who won a 2010 US Open quarter-final in five sets in their most recent meeting.
Djokovic, 26, seeks his 14th consecutive Grand Slam semi-final since losing to Jurgen Melzer in the 2010 French Open quarter-finals, his run second only to Federer's 23 in a row ending at the 2010 Australian Open.
Bidding for his seventh US Open semi-final in a row and a fourth consecutive trip to the final, Djokovic has not dropped a set in the New York fortnight.
Youzhny, 24, is 0-10 all-time against world number one. He seeks his third trip to the US Open semi-finals after 2006 and 2010.