Australia's big last hope floundered in a sea of forehand errors to succumb 6-3 7-5 6-2 to inspired Englishman Jack Draper on Wednesday (Thursday AEST).
De Minaur had been fancied to reach his maiden grand slam semi-final against the lower-ranked Draper, especially having beaten the 22-year-old in all three previous encounters.
Britain's Jack Draper returns during his straight-sets defeat of Alex de Minaur in New York. (AP PHOTO)
But the world No.10 struggled to find top gear at Arthur Ashe Stadium as Draper continued his own march through the Open draw.
It was unclear if de Minaur was fighting the hip injury that had sidelined the 25-year-old since Wimbledon.
De Minaur clutched at the leg on occasions while trying to transition in points.
Other times, he flew around centre court with signature lightning speed.
All the while Draper delivered a masterclass to end Australia's singles interest in the final grand slam of the year.
As de Minaur's horror unforced error count grew the classy left-handed Brit dictated from the get-go with powerful groundstrokes, big serving and a succession of sumptuous forehand drop shots.
Draper's reward is a first grand slam semi-final appearance on Friday against either world No.1 and reigning Australian Open champion Jannik Sinner or fifth-seeded 2021 US Open winner Daniil Medvedev.