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Pironkova, playing her first tournament in three years after a lengthy break in which she gave birth to her son, prevailed 6-4, 6-7 (5/7), 6-3 at the Louis Armstrong Stadium.

“It’s absolutely unreal, I really can’t believe it,” said Pironkova, whose last tournament appearance before this year’s US Open was the 2017 Wimbledon championships when she exited in the second round.

Mertens ousted Kenin, this year’s Australian Open champion, 6-3, 6-3 in 1hr 14 mins to set up a last-eight tie with former world number one Victoria Azarenka.

The Belarusian overcame 20th seed Karolina Muchova of the Czech Republic 5-7, 6-1, 6-4 in 2hr 30min at Louis Armstrong Stadium.

In the men’s draw, second-seeded Thiem raced into the round of eight with a three-set demolition of Canadian rising star Felix Auger-Aliassime.

Thiem dismantled the 20-year-old 15th seed 7-6 (7/4), 6-1, 6-1 in 2hr 7min.

“I played a great match today, the best one from my whole America trip,” said Thiem.

He will play Australia’s 21st seed Alex de Minaur for a spot in the semi-finals after the Australian breezed past unseeded Canadian Vasek Pospisil 7-6 (8/6), 6-3, 6-2, in 2hr 17 min.

Third seed Medvedev blew away unseeded American France Tiafoe 6-4, 6-1, 6-0 in only 1hr 38 min.

“I’m pleased with the fact that I’ve won all of these sets and didn’t have to stay long on the court. That’s always good when you’re playing a Grand Slam,” said the Russian.

Medvedev will face compatriot Andrey Rublev for a spot in the last four after the 10th seed ousted Italy’s sixth seed Matteo Berrettini 4-6, 6-3, 6-3, 6-3.

The men’s competition was blown wide open on Sunday after world No 1 Novak Djokovic was thrown out for accidentally hitting a line judge after smashing a ball in frustration during his last-16 match.

His departure means the US Open will this year produce a first-time Grand Slam winner in the men’s competition.

Williams is seeking to equal Margaret Court’s record for the most women’s Grand Slam singles titles.

A tournament victory at the weekend would also see her break away from Chris Evert, on six titles, as the most decorated US Open champion of the women’s game in the modern era.

Results from US Open tennis championship in New York on Monday (x-denotes seed)

Men’s singles

Fourth round

Andrey Rublev (RUS x10) bt Matteo Berrettini (ITA x6) 4-6, 6-3, 6-3, 6-3

Alex De Minaur (AUS x21) bt Vasek Pospisil (CAN) 7-6 (8/6), 6-3, 6-2

Dominic Thiem (AUT x2) bt Felix Auger-Aliassime (CAN x15) 7-6 (7/4), 6-1, 6-1

Daniil Medvedev (RUS x3) bt Frances Tiafoe (USA) 6-4, 6-1, 6-0

Women’s singles

Fourth round

Tsvetana Pironkova (BUL) bt Alize Cornet (FRA) 6-4, 6-7 (5/7), 6-3

Serena Williams (USA x3) bt Maria Sakkari (GRE x15) 6-3, 6-7 (6/8), 6-3

Victoria Azarenka (BLR) bt Karolina Muchova (CZE x20) 5-7, 6-1, 6-4

Elise Mertens (BEL x16) bt Sofia Kenin (USA x2) 6-3, 6-3