Rafael Nadal has been eliminated at the US Open in his first grand slam loss of the year.

The Spanish legend was knocked out by red hot American underdog Francis Tiafoe in a four-set rollercoaster.

Tiafoe, ranked No 22, pulled off the biggest win of his career to beat second-seeded Nadal 6-4, 4-6, 6-4, 6-3 to reach the US Open quarter-finals.

Tiafoe buried his head in his hands and cried on the court after he shook hands with Nadal. He sat on the bench and buried his head in a towel as Nadal walked off and waved to the crowd.

The win has likely cost Nadal the No 1 ranking.

The victory sends Tiafoe into a quarter-final meeting with Russian ninth seed Andrey Rublev on Wednesday.

The 24-year-old Tiafoe is the youngest American to reach the quarter-finals since Andy Roddick did so at 24 in 2006.

Nadal, a four-time US Open champion, was the highest-seeded player left after No 1 Daniil Medvedev lost on Monday to Nick Kyrgios.

Tiafoe already was the first American man to reach the fourth round in three straight years since Mardy Fish in 2010-12.

Frances Tiafoe celebrates. Photo / AP

Nadal entered 22-0 at Grand Slam events in 2022. He was 21-1 against Americans since October 2017, which included straight-set wins over Tiafoe in the 2019 Australian Open quarter-finals and 2019 Madrid third round.

The early edge was a boon for Tiafoe. Nadal has never come back from down 2-1 at the US Open and fell to 0-7 overall at Flushing Meadows with that deficit.

Women's No 1 seed Iga Swiatek survived a slow start to knock off unseeded Jule Niemeier 2-6, 6-4, 6-0 to reach the quarter-finals at the US Open for the first time.

Swiatek, a two-time French Open champion, will play Jessica Pegula next.

Iga Swiatek celebrates after defeating Jule Niemeier. Photo / AP

Jessica Pegula eliminated two-time Wimbledon champion Petra Kvitova 6-3, 6-2 to get to her third major quarter-final of 2022 and reach that round for the first time at Flushing Meadows.

Earlier, Andrey Rublev reached his sixth Grand Slam quarter-final by beating Cam Norrie 6-4, 6-4, 6-4 in a match delayed by about 25 minutes while the retractable roof at Louis Armstrong Stadium remained open during a downpour.

The No 9-seeded Rublev is into his third quarter-final at Flushing Meadows. Rublev next faces Tiafoe.

- with news.com.au