Australia's Nick Kyrgios sent defending champion Daniil Medvedev tumbling out of the US Open on Sunday as US teenager Coco Gauff reached the quarter-finals for the first time.

The notoriously temperamental 23rd-seeded Kyrgios produced some scintillating shot-making on his way to a superb 7-6 (13/11), 3-6, 6-3, 6-2 win over the world number one from Russia.

Kyrgios, who was beaten by Novak Djokovic in the Wimbledon final in July, showed grit and composure to save three set points in the opening set before holding his nerve to win an epic tie-break 13/11 before a raucous Arthur Ashe Stadium crowd.

Although he dropped the second set, he roared back to dominate Medvedev in the third and fourth sets to clinch victory in 2hr 53min.

"It was an amazing match, obviously Daniil as the defending champion had a lot of pressure on his shoulders, but I've been playing amazing the last couple of months," Kyrgios said after the win.

"What a place to do it -- packed house in New York. I'm extremely blessed."

Kyrgios will face Karen Khachanov in the quarter-finals on Tuesday. Khachanov equalled his best performance in a Grand Slam event by defeating Spanish 12th seed Pablo Carreno Busta in a 3hr 21min five-set thriller.

The 27th-seeded Khachanov dug deep to down Carreno Busta 4-6, 6-3, 6-1, 4-6, 6-3 on the Louis Armstrong Stadium.

Elsewhere in the fourth round on Sunday, fifth seed Casper Ruud became the first Norwegian man to reach the US Open quarter-finals with a 6-1, 6-2, 6-7 (4/7), 6-2 victory over French lucky loser Corentin Moutet.

The 23-year-old Ruud, seeded fifth, will face Italy's Matteo Berrettini for a place in the semi-finals.

Berrettini extended his impressive run of recent Grand Slam singles performances with a 3-6, 7-6 (7/2), 6-3, 4-6, 6-2 defeat of Spain's Alejandro Davidovich Fokina.

The 26-year-old from Rome missed Wimbledon earlier this year after testing positive for Covid-19, and was injured for the French Open.

But Berrettini has now made the quarter-finals or better in the last five Grand Slams he has played in after Sunday's win.

"It's not a secret for me the Slams are the goal of the season," he said.

"I think it proves that my level is high in Slams ... I play my best tennis in the most important stages of the tour."