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Australia's former quarter-finalist John Millman has suffered a five-set second-round US Open loss to American Frances Tiafoe at Flushing Meadows.

John Millman is lamenting opportunities lost after coming off second best in a brutal second-round baseline slugfest at the US Open in New York.

Australia's 2018 quarter-finalist let slip a two-sets-to-one lead to bow out 7-6 (8-6) 3-6 1-6 6-3 6-3 to talented young American Frances Tiafoe in a four-hour heartbreaker.

"It's always tough losing those tight ones. It's going to hurt," Millman said.

"I didn't play bad tennis. I thought Frances caught fire there for about a set and a half and he's got that explosive game where he can do that.

"Obviously I would have loved to have won and that's what I'm here to do, is win big matches in these big tournaments.

"I didn't plan to lose today and I wanted to progress further."

Triumphant over Roger Federer at Flushing Meadows two years ago in the defining grand slam performance of his career, Millman ultimately paid the price for only managing to convert seven of 23 break-point chances.

"Tennis is a game of really fine margins and I think this one showed that," he said.

"On a couple of really big points, I was missing a couple of the lines by less than a centimetre and I felt on a couple of his big ones he was scraping the line.

"I felt I probably didn't get the rub of the green today."

Millman's exit leaves Alex de Minaur and Jordan Thompson to fly the Australian flag in the singles in New York.