Ninth-seeded Wawrinka dominated an out of sorts Murray 6-4 6-3 6-2 in just over two hours, winning the battle from the baseline and the net against the Wimbledon champion.
The victory on a wind-blown Arthur Ashe Stadium court lifted the 28-year-old Swiss to his first Grand Slam semi-final.
The surging Wawrinka, who raised his 2013 record to 41-15 with the upset win, raised both arms in triumph after third seed Murray dumped a second-serve return into the net on match point.
"It feels amazing for sure, especially here," the excited Swiss said. "He's defending champion, he's a tough opponent. It was a crazy match for me. To beat him in three sets is just amazing."
Wawrinka broke the Scotsman four times and never faced a break point against a player noted for his ability to return.
The Swiss cracked 45 winners past a listless Murray and won 31 of 42 forays to the net in the one-sided match.
The match turned in Wawrinka's favour at the end of the opening set, which was on serve at 5-4 to the Swiss but ended in an enthralling 10th game.
Murray made several errors but still managed to save five set points. He finally gave up the set when he sent a forehand long and responded by angrily smashing his racquet onto the court.
The frustration might have indicated a more aggressive Murray to come but his struggles extended to the second set where he allowed his opponent triple break point in the sixth game, which Wawrinka took advantage of with a superb backhand winner down the line.
Wawrinka held his serve to take the second set and his joyful reaction illustrated his belief that a first Grand Slam semi-finals appearance was within his reach.
A double fault on break point from Murray in the third game of the final set summed up his afternoon and the match was put beyond him with a brilliant forehand winner from the Swiss broke Murray again to go up 5-2.
For the Scotsman, the defeat marked his second loss to Wawrinka this year, having fallen in a last-16 clash on clay at the Monte Carlo Masters in April.
Murray admitted to something of a Wimbledon hangover after ending a drought of 77 years without a British men's winner since Fred Perry's 1936 triumph at the All England Club.
"When you work hard for something for a lot of years, it's going to take a bit of time to really fire yourself up and get yourself training 110 per cent," the Scotsman said.
"That's something that I think is kind of natural after what happened at Wimbledon. But I got here. I got to the quarter-finals of a slam, which isn't easy."
Much more was expected of Murray, as it was for the other Swiss player that factored at Flushing Meadows - Roger Federer.
Murray's loss was the second seismic shocker to strike the men's draw in the last two rounds following the straight sets dismissal of five-time US Open champion Federer in the fourth round by Spain's Tommy Robredo.
Robredo's rousing victory robbed fans of a quarter-finals match between Federer and Rafa Nadal that would have marked the first US Open meeting ever between the two champions, who have met 31 times elsewhere around the world.
Wawrinka's victory sank the possibility of a Murray semi-final against top seed Novak Djokovic that would have reprised their 2012 US Open and 2013 Wimbledon finals.
Djokovic was playing the last men's quarter-final against 21st-ranked Mikhail Youzhny of Russia in Thursday's night match. Murray complained about the breezy conditions, but credited Wawrinka for playing a brilliant match.
"He played great. He hit big shots. He passed extremely well. He hit a lot of lines on big points. He served well. That was it," said Murray. "He played a great match."
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