Wawrinka, ranked tenth in the world and seeded ninth in tournament, downed the third-ranked Scot in three sets in a quarterfinal shocker at Arthur Ashe stadium.
It was an echo of the third round of the US Open three years ago when the Swiss also beat Murray.
The 28-year-old Lausanne native reached his first Grand Slam semifinal by again defeating the now reigning Olympic and Wimbledon champion, booking a Saturday last-four date against either Russian 21st seed Mikhail Youzhny or world number one Novak Djokovic.
Oddsmakers would make Serbia's Djokovic the likely winner of that matchup, but this has been a US Open full of surprises.
Swiss media noted that Wawrinka's win marks the first time since Marc Rosset qualified for the semifinals at Roland Garros 17 years ago that a player from French-speaking Switzerland had made it to the semis of a Grand Slam tournament.
The victory comes after he upset fifth-ranked Tomas Berdych of the Czech Republic in the fourth round.
"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," he said.
"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.
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," Wawrinka said.
"It was very windy — we were trying to find the game," he said.
"To get that gave me a little bit of confidence for sure."
Spanish second seed Rafael Nadal and French eighth seed Richard Gasquet will meet in Saturday's other semifinal.