Australia’s shooting star was unable to back up his mighty third-round win over the great Novak Djokovic, succumbing 6-4 7-6 (7-3) 2-6 6-3 to his friend and foe Tiafoe on Sunday night in New York.

Leaving Alex de Minaur and Jordan Thompson to fly the flag in the men’s singles, Popyrin will rue a huge opportunity lost.

The 25-year-old entered the most significant match of his life having claimed six top-20 scalps in his previous eight outings, with none bigger than that of 24-times major winner and defending champion Djokovic.

But the Montreal Masters champion was unable to conjure the magic of 48 hours earlier as the partisan crowd on Arthur Ashe Stadium, cheering seemingly every Tiafoe winner and Popyrin error, willed the home hope to a rousing victory.

A semi-finalist in 2022 and quarter-finalist last year, Tiafoe will face Bulgarian ninth seed Grigor Dimitrov in the last eight this time around.

Popyrin will feel like he let slip a great chance to reach a maiden grand slam quarter-final after making a blazing start to the match.

Confident on serve and deadly from the back, Popyrin dominated early but paid the price for not breaking Tiafoe in the fourth game when he had his regular hitting partner on the back foot serving at 15-40.

He then dropped his own serve out of nowhere to fall behind 5-4.

Tiafoe closed out the set to love before even worse was to come for Popyrin in the second.

Once again he was largely untroubled on serve and, after breaking Tiafoe for the first time in the fourth game, Popyrin had the set on his racquet at 5-3, 40-0.

But he squandered all three set points and must have been cursing himself after being broken to invite Tiafoe back into the set.

Tiafoe, feeding off frenzied crowd support, didn’t need a second invitation.

He pushed the set to a tiebreaker, and Popyrin made a horror start with a double fault as Tiafoe charged to a 3-0 lead.

Popyrin clawed his way back into it but, upset at a spectator interrupting his serve, Popyrin gave the fan a right glare after double-faulting again to hand Tiafoe set point.

With a big ace, the home favourite surged to a commanding two-sets-to-love lead.

Not done, Australia’s 28th seed dug in to gain a foothold with a near-flawless third set to create doubts in the American’s mind.

Alas, it was Popyrin who blinked first, double-faulting twice more in the sixth game of the fourth set to gift Tiafoe a decisive break.

The 20th seed showed his nerve to save a break point and serve out the match three games later after three hours and two minutes, becoming the first American since Andy Roddick in 2006-08 to make the US Open quarter-finals for three straight years.

De Minaur, the 10th seed, will square off with Thompson on Monday (7am Tuesday AEST) in an all-Australian fourth-round battle on Louis Armstrong Stadium.