Roger Federer has been knocked out of the US Open in the fourth round by world number 55 John Millman.

The 37-year-old Swiss had prioritised winning a sixth title at Flushing Meadows but was beaten 3-6 7-5 7-6 (9-7) 7-6 (7-3) in three hours 38 minutes.

It is the first time Federer has lost to a player ranked outside of the top 50 at the US Open.

Australian Millman will play two-time champion Novak Djokovic in his first Grand Slam quarter-final on Wednesday,

Second seed Federer, bidding for a record-extending 21st Grand Slam, missed set points in the second and third sets before capitulating in the fourth-set tie-break.

Millman, 29, had never beaten a top-10 player before but suddenly found himself with five match points against arguably the greatest male player of all-time.

After Federer rallied to save two of the them, Millman completed victory at almost 01:00 local time in New York when the out-of-sorts Swiss lumped a forehand long.

It was Federer’s first defeat in 41 matches at the US Open against a player ranked outside the top 50.

Warning signs were clear for Federer

After not dropping a set in his opening three matches, Federer looked on his way to another controlled victory when he eased the opener in 33 minutes.

However, the warning signs were clear from the start of the second set.

Federer’s reliable serve has been the bedrock of his game over the years but an uncharacteristically erratic display allowed Millman to fight back and earn a memorable win.

The world number two produced a contender for one of the ugliest service games of his career, unable to find his timing as he landed just six of his 24 first serves in a 14-minute second game.

He somehow managed to hold after fighting off seven break points, before breaking Millman’s serve himself to lead 3-2.

But, with his first serve percentage down at 31%, Federer still looked uncomfortable.

He blew two set points when serving at 5-4 and a double fault at break point gifted Millman the game and the Australian broke again as he won four games in a row to level the match.

Willed on by a supportive crowd on Arthur Ashe Stadium, Federer managed to steady his service game in a tight third set and missed a set point in the tie-breaker when Millman hit an outrageous 100mph second serve down the middle.

The Australian wasted one of his own with a long return as Federer battled to stay in the set, only to take his second chance and leave Federer facing an uphill task.

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Britain’s Jamie Murray and his Brazilian partner Bruno Soares reached the men’s doubles quarter-finals at the US Open without dropping a set in three matches.

The fourth seeds, who won the title in 2016, beat Dutchmen Robin Haase and Matwe Middelkoop 7-6 (7-4) 6-4.

They face unseeded Radu Albot of Moldova and Tunisia’s Malek Jaziri in the last eight.

Murray is back on court later in the day for a mixed doubles quarter-final.

He and American partner Bethanie Mattek Sands take on Nadiia Kichenok and Wesley Koolhof.

Fellow Briton Dom Inglot and Croatian partner Franko Skugor saw their run in the competition ended by American third seeds Jack Sock and Mike Bryan, who won 6-2 6-4.

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Last year’s runner-up Madison Keys is through to the quarter-finals of the US Open after she defeated 29th seed Dominika Cibulkova 6-1 6-3.

American 14th seed Keys broke twice in the first set and again on Cibulkova’s first game in the second.

She dropped serve shortly afterwards but broke back twice to win in one hour and 16 minutes on Arthur Ashe.

Keys will face the winner in the match between Maria Sharapova and Carla Suarez Navarro in the quarter-final.

She said: “I am glad I got the win and can come out here again for another match. It’s always easier to be more energised when the person on the other side of the net is more energised than you can possibly be.

“She’s a good player and has done a lot in her career. It was about having to focus on first serves and waiting for the right ball. I had to move my feet and used the crowd in those tight moments.”

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Serena Williams says her motivation to win major trophies remains as high as ever in motherhood after reaching the US Open quarter-finals.

Williams, whose daughter Olympia turned one on Saturday, is aiming to win a record-equalling 24th Grand Slam title in New York.

The 36-year-old American former world number one is playing her seventh tournament since giving birth.

“That desire has not gone down at all,” she said.

“And I don’t think it was capable of going up, because if it was at a 10, I was at a 15 or a 20 – and I’m still there.”

Williams, seeded 17th, has been in fine form at Flushing Meadows, dropping her first set of the tournament before recovering to win 6-0 4-6 6-3 against Estonia’s Kaia Kanepi on Sunday.

Winning the US Open for a seventh time would see her level Australian Margaret Court’s all-time record of 24 majors.

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Williams returned to Slam competition at the French Open in May, only to withdraw before her last-16 match against Maria Sharapova of Russia because of injury.

She then reached the Wimbledon final in July but lost to Germany’s Angelique Kerber.

“My desire still remained at that incredibly high level to compete and to want to win,” Williams said.

“It would be wonderful to win a Grand Slam while having a daughter, but it’s a lot of work.

“It takes a lot of work to win those tournaments. I’m only in my third one back. I’m going to continue to grind and see what happens.”

Meanwhile, Williams says she hopes to have more children in the future – but maybe not until after she finishes playing.

“Right now is not the time,” she said. “I’m thinking about playing tennis and enjoying this time with Olympia.

“I’ll have plenty of time in the future.”

‘It was a Serena scream’

Williams cruised to the first set in 18 minutes against Kanepi, only to see the world number 44 fight back to level in the second.

The Estonian missed two break points in the first game of the third set, allowing Williams to fight back and hold serve with a backhand winner, which brought out a loud yell of “come on” from her.

“It was a Serena scream,” Williams said with a smile. “I don’t try to do it. It just comes out.

“Winning a big game and a very important game and a really tight game, I think it was just a relief.”