Australia's world No.7 slumped to a shock straight-sets loss to Botic van de Zandschulp, a Dutchman he'd beaten in all four of their previous meetings.
In a demoralising display, de Minaur dropped serve five times and only broke his 70th-ranked opponent once in a 6-4 7-5 6-2 defeat on Thursday (Friday AEST).
He also racked up 30 unforced errors compared to just 23 winners in the two-hour, 43-minute upset on The Grandstand.
"My level today wasn't good enough. It's pretty straightforward," de Minaur said.
"I gave myself every chance by being competitive, having a good mindset, a good attitude, but it was just one of those days where just the feeling of the ball on the strings wasn't there.
"I was making a lot of errors, which is not really my normal game style. I can't really explain the reasoning of it, but just it felt like the more I tried, the more intensity, the more fired up I was getting, I just kept on making unforced errors.
"When those sort of things happen and the odd chance that you have, he comes out with some good tennis - it's just a recipe for a tough day at the office."
A three-times US Open quarter-finalist, including on his past two visits to Flushing Meadows, de Minaur had been the fourth-highest-ranked player left in the draw following the exits of Novak Djokovic and Felix Auger-Aliassime.
His Italian nemesis and world No.1 Jannik Sinner, who holds a 13-from-13 record over the Australian, is also missing with a knee injury, while defending champion Carlos Alcaraz is playing his first tournament in four months.
But the sixth seed was unable to cash in.
De Minaur was almost disconsolate following his Wimbledon quarter-final loss to Flavio Cobolli in July.
But maybe it's married life. Maybe not.
For whatever reason, the 27-year-old was able to shake off this loss, his earliest defeat in New York in five years, much more easily.
"No, I'm good," he said.
"Obviously would have loved to do better, as any competitor would, but it's what happens in this sort of sport. Everyone loses matches.
"Everyone is losing matches that maybe they would love to have back.
"I've had some incredible moments on the tennis court and there's been some days where I've been a shadow of myself and I've struggled to make the court.
"What I've been fortunate in my career is that there hasn't been too many of those days.
"So, all in all, it's one I would love to have back, but we move forward and it's not the end of the world."
De Minaur's surprise departure incredibly leaves little-known wildcard Dane Sweeny as Australia's last player standing at the season's final grand slam event.
The world No.123 will play 21st seed Luciano Darderi on Saturday (Sunday AEST) for a most improbable spot in the last 16 after taking out Darderi's 14th-ranked compatriot Lorenzo Musetti 3-6 6-1 6-2 6-2 in a huge second-round boilover.
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