Alexei Popyrin's US Open run is over, falling to a four-set defeat against American number 20 seed Frances Tiafoe in the fourth round.

Tiafoe was able to make the most of his chances to win 6-4, 7-6 (6-3), 2-6, 6-3 in front of a parochial home crowd on Arthur Ashe court.

Having beaten number two-seed Novak Djokovic in the third round, Popyrin had hoped to ride his form deep into the second week of a grand slam for the first time.

However, the 26-year-old American had other ideas, claiming the first two sets as unforced errors and a couple of crucial missed opportunities cruelled Popyrin's chances.

"Look, I'm telling everybody now, if you would have told me at the start of the summer I would have been 23 in the world with a Masters title and second week of a slam for the first time, I probably would have taken it considering the position I was in," Popyrin said.

"If I hadn't won a match in Montreal or Cincy, I probably would have dropped to outside 90 in the world.

"It definitely does feel like a little opportunity lost. This match, it was changed by I think one, two, or three points.

"He won three more points than I did all match, and he won three sets. That just shows you how close it was."

His defeat leaves Alex De Minaur, the 10th seed, and Jordan Thompson, who meet on Monday (7am Tuesday AEST) as the only Australians remaining in the singles draw. 

Popyrin fought back to claim the third set, but two double faults in the crucial sixth game of the fourth saw the Australian 28th seed's chances evaporate.

Despite enjoying his best ever performance at a grand slam — never before had Popyrin reached the second week of a major — the 25-year-old will be left ruing his missed opportunities.

The Australian led 5-2 and was serving for the second set, only to surrender his advantage and lose 7-3 in a tie break.

"It's a really big choke from my end," Popyrin said, while Tiafoe admitted in his post-match, on-court interview that he "got pretty lucky".

“He was serving 5-3, 40-0, I’m sweating through my shoes thinking I’m about to go change my clothes," Tiafoe said.

"And I’m just thinking, OK what if I get this next [point], and I did. Then I thought, OK, what about this next one, and I did. And then I won that one.”

The Aussie also missed two break points in the first set to that would have given him an early 3-1 lead.

He even had a break point as Tiafoe served for the match, but netted with a forehand after a sublime rally to send the game to deuce.

And after that, Tiafoe needed no second invitation.

Tiafoe joined Andre Agassi, Andy Roddick and Pete Sampras as the only American men to reach the US Open quarterfinals three times or more this century.

"From [when I was] a kid, hitting a ball against a wall, I wanted to compete on this court," Tiafoe said.

"Seeing the Williams sisters win titles here, seeing Roger win a million times, I was like, I just wanna play on this court. It's so iconic.

"It brings out the best in me." 

He meets Bulgarian number nine seed Grigor Dimitrov in the quarterfinals. 

ABC/AAP