De Minaur had the chance to climb into the world's top five with a deep run at the final Masters 1000 event before the season's last grand slam in New York.
But the Australian No.1 delivered a flat performance to fall 6-3 6-4 to rising Frenchman Arthur Fils in just 82 minutes on Wednesday (Thursday AEST).
Fils, the first Frenchman since Jo-Wilfried Tsonga in 2012 to reach five Masters quarter-finals in a single season, next plays Argentine Thiago Agustin Tirante, a 5-7 6-4 6-4 winner over Czech 14th-seed Jakub Mensik.
De Minaur dropped serve once in each set and was unable to break the 21st seed at all.
The world No.8's exit means de Minaur is certain to be seeded in the top eight at Flushing Meadows, still ensuring the Australian doesn't run into a higher-ranked player until at least the quarter-finals.
But with Carlos Alcaraz still injured, de Minaur could have snatched a US Open top-four seeding and been guaranteed to avoid heavyweights such as Jannik Sinner and Alexander Zverev until at least the semi-finals.
In another upset, American Tommy Paul saved a match point to defeat top-seed Zverev 4-6 7-6 (8-6) 6-4 and reach the quarter-finals after a nearly 90-minute rain delay.
German world No.3 Zverev took the first set and trailed 3-4 in the second before the fourth-round match was suspended due to rain.
Paul emerged from the lengthy delay looking the sharper player, saving a match point before levelling the contest as Zverev struggled to find his rhythm.
The German took a 4-2 lead in the third set but Paul dug in to take control of the match, rallying to win four straight games to advance to the quarter-finals in Cincinnati for the first time.
"Not really sure," Paul said when asked how he had turned the match around.
"I guess just put some returns in. He gave me a couple of looks at second serves and a couple of doubles there, that helped me out a ton."
Paul next plays Flavio Cobolli in his 50th tour-level quarter-final after the Italian earlier defeated Spanish young gun Rafael Jodar 4-6 7-6 (7-3) 6-3.
Sixth-seed Taylor Fritz ended the run of Australian qualifier Chris O'Connell with a 6-4 6-3 victory.
Fritz will play fellow American Brandon Nakashima, who ousted Portugal's Nuno Borges 6-3 6-7 (5-7) 6-3.
Australian teenager Cruz Hewitt, meanwhile, has been awarded a wildcard into next week's Winston-Salem Open.
- with Reuters
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