Ninth-seeded Wawrinka made his first Grand Slam semifinal, earning a spot in the final four for Switzerland that for so long felt like Roger Federer's birthright.
"It feels amazing for sure, especially here," Wawrinka said.
"Especially after that match. He's the defending champion, he's a tough opponent."
Wawrinka will play the winner of Thursday's late quarter-final between No 1 Novak Djokovic and No 21 Mikhail Youzhny.
After years of close calls and deep trips into majors, the third-seeded Murray finally won his first Grand Slam title at Flushing Meadows last year, then his second at Wimbledon this July.
But the straight-set loss to Wawrinka ended a stay in New York during which he never got completely comfortable - not when he had to wait until the first Wednesday to begin the defence of the title, not when he struggled in a four-set victory over Denis Istomen in the fourth round and certainly not on Thursday.
This was Murray's earliest exit from the US Open since 2010, when Wawrinka also did the honours that year in the third round.
Murray conceded it's been a long road since he broke into the top, first at the Olympics on home turf last year, then with the two major titles.
"When you work hard at something for a lot of years, it's going to take time to fire yourself up and get to training 110 per cent," Murray said about his preparation for the year's final Grand Slam.
"That's something kind of natural after what happened at Wimbledon."
An amazing letdown, especially considering the numbers he has been putting up of late.
He had appeared in the finals of the previous four major tournaments he entered.
He had won 30 of his last 32 Grand Slam matches.
He had been 7-0 on hard courts in major quarter-finals.
This marked his first straight-set loss in a major since the semifinals of the 2011 French Open.
"If I'm meant to win every Grand Slam I play or be in the final, it's just very, very difficult just now," Murray said. "With the guys around us, it's very challenging."
Wawrinka is certainly one of those guys now.
He played near-flawless tennis.
He also charged the net, not allowing Murray to get comfortable.
- AP