Nick Kyrgios and Thanasi Kokkinakis passed up two match points before being eliminated in the US Open doubles at the round of 16 stage on Tuesday (AEST).
The Australian eighth seeds had the opportunity to close the contest out in straight sets but eventually were overwhelmed 3-6 7-6(6) 7-6(8) by 11th-seed duo Lloyd Glasspool and Harri Heliovaara.
In their first pairing at a major since winning the Australian Open, Kyrgios and Kokkinakis raced to a comfortable lead in the match, claiming the first set 6-3.
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Games remained on serve throughout the second set before the Australians earned two match points on Kyrgios' serve in the tiebreak.
However the English-Finnish duo managed to save both before winning another two points consecutively to tie the match at one set apiece.
The third set was another tight battle with Kyrgios and Kokkinakis fighting back from a break down in their first service game to level the match and force a deciding tiebreak.
But after leading on multiple occasions during the final breaker, including 3-1 and 8-6, the Australians eventually succumbed by losing four straight points.
Defeat for Kyrgios will allow him to focus on his US Open singles campaign, where he is favourite to win his first Grand Slam title after knocking out world No.1 Daniil Medvedev.
Kyrgios meets 27th seed Russian Karen Khachanov in the quarter-finals on Wednesday (AEST) as he continues his mission to qualify for his second consecutive Grand Slam finals after just falling short of winning at Wimbledon.
Tennis legend Novak Djokovic denied Kyrgios glory at Wimbledon, but the three-time US Open winner isn't involved in this tournament because of his vaccination status.
The nature of this year's US Open draw sees Kyrgios have a relatively straight-forward path to the final - with tough matches but no tennis monoliths in his path.
Khachanov is a good player and has a 1-1 record against Kyrgios - both on hard courts - but the Russian has never been past the quarter-finals of a Grand Slam and is coming off a gruelling five-set match against Pablo Carreno-Busta.
If Kyrgios manages to negotiate his way past Khachanov, the winner of fifth seed Casper Ruud and world No.14 Matteo Berrettini will be waiting in the semis for a place in the final.
