Daniil Medvedev's US Open title defence evaporated in front of a packed crowd at Arthur Ashe Stadium in a four-set loss to Australia's Nick Kyrgios, while American teenager Coco Gauff kept home hopes alive after seeing off Zhang Shuai on Sunday.
Kyrgios, Wimbledon finalist this year, has recorded the most wins on tour since the end of the French Open and continued the finest season of his career with a 7-6(11), 3-6, 6-3, 6-2 victory over Medvedev in a blockbuster fourth-round clash.
"If (Kyrgios) plays like this till end of the tournament, he has all the chances to win it," said Medvedev, who will lose his world No. 1 ranking after his defeat.
Kyrgios will face Karen Khachanov after the Russian beat 12th seed Pablo Carreno Busta in a tough five-setter. Khachanov edged out twice semifinalist Busta 4-6, 6-3, 6-1, 4-6 ,6-3 to reach his third major quarterfinal and first in New York.
Kyrgios's compatriot Ajla Tomljanovic also made the quarter-finals of the women's draw after a gritty straight-sets victory over Liudmila Samsonova.
Rising star Gauff, 18, battled to a 7-5, 7-5 win over China's Zhang and will play the in-form Caroline Garcia for a place in the semifinals after the Frenchwoman defeated Alison Riske-Amritraj 6-4, 6-1.
Tunisian fifth seed Ons Jabeur, runner-up at Wimbledon, extended her career-best run in New York by beating Veronika Kudermetova 7-6 (1), 6-4 to set up a meeting with Tomljanovic.
Earlier, Italy's Matteo Berrettini dug deep to prevail 3-6, 7-6(2), 6-3, 4-6, 6-2 over Alejandro Davidovich Fokina in a three-hour, 45-minute marathon to reach his second straight quarterfinal at Flushing Meadows.
Up next for Berrettini is fifth seed Casper Ruud, who ended lucky loser Corentin Moutet's fairytale run with a 6-1, 6-2, 6-7(4), 6-2 triumph.