All eight players remaining in New York have never won a major title, meaning there’s everything to play for in a wide open draw.
Twenty-two-time Slam champion Nadal, 36, lost to Frances Tiafoe on Monday night in the Spaniard’s first defeat in a top event during this calendar year.
Frances Tiafoe celebrates his win over Rafael Nadal to reach the US Open quarter-finals
Nadal waves goodbye after his defeat and said he didn’t know when he would play again
Nick Kyrgios got the better of reigning champion Daniil Medvedev in their fourth round match
Russian Medvedev, 26, who won last year’s US Open, went out to Wimbledon finalist Nick Kyrgios in his fourth round encounter.
Cilic, meanwhile, who won in New York back in 2014 – his only Slam win – was beaten by Spaniard Carlos Alcaraz in a five-set epic.
Nick Kyrgios vs Karen Khachanov
Matteo Berrettini vs Casper Ruud
Jannik Sinner vs Carlos Alcaraz
Andrey Rublev vs Frances Tiafoe
Also through to the quarter-finals are Karen Khachanov, Matteo Berrettini, Casper Ruud, Jannik Sinner and Andrey Rublev, who are all trying to win their first Slam title.
Berrettini reached last year’s Wimbledon final, losing to Novak Djokovic, while Ruud was beaten by Nadal in the French Open final earlier this year.
Khachanov, Sinner and Rublev have never progressed beyond the quarter-finals at one of the big four events, so have now matched their best runs.
Exciting Spanish talent Alcaraz, 19, has also never got past the last eight in a Slam.
The quarter-final matches will see Kyrgios play Khachanov, Berrettini face Ruud, Sinner play Alcaraz and Rublev take on Tiafoe.
They are set to be played on Tuesday and Wednesday.
Nadal admitted he doesn’t know when he will play again after losing in the fourth round to Tiafoe. His wife Maria is pregnant with their first child.
2014 US Open champion Marin Cilic (right) was beaten over five sets by Carlos Alcaraz
Matteo Berrettini celebrates his win over Andy Murray earlier in the Flushing Meadows Slam
‘I need to go back. I need to fix things, life, then I don’t know when I’m going to come back,’ Nadal said.
‘I’m going to try to be ready mentally. When I feel that I will be ready to compete again, I will be there.’
Nadal is scheduled to take part in the Laver Cup alongside Roger Federer, Djokovic and Andy Murray, in London between September 23-25.
Russian Rublev got the better of Great Britain’s Cameron Norrie in their fourth round encounter, winning in straight sets.
Alcaraz, who remains in contention to pip Nadal to the number one ranking, completed a 6-4, 3-6, 6-4, 4-6, 6-3 victory over Cilic at close to 2.30am.
In the last eight he will take on fellow young gun Sinner, who also needed five sets to defeat surprise package Ilya Ivashka 6-1, 5-7, 6-2, 4-6, 6-3.
Their previous best at Slams
Nick Kyrgios – Wimbledon final 2022
Karen Khachanov – French Open quarter-final 2019; Wimbledon quarter-final 2021; US Open quarter-final 2022
Matteo Berrettini – Wimbledon final 2021
Casper Ruud – French Open final 2022
Jannik Sinner – French Open quarter-final 2020; Australian Open quarter-final 2022; Wimbledon quarter-final 2022; US Open quarter-final 2022
Carlos Alcaraz – French Open quarter-final 2022; US Open quarter-final 2021 and 2022
Andrey Rublev – US Open quarter-final 2017, 2020 and 2022; French Open quarter-final 2020 and 2022; Australian Open quarter-final 2021
Frances Tiafoe – Australian Open quarter-final 2019; US Open quarter-final 2022