Defending champion Novak Djokovic reached the US Open last 16 in just 32 minutes Friday when Mikhail Youzhny retired at 2-4 down in the first set of their third round clash.

Russian 34-year-old Youzhny had needed treatment on a left leg injury after five games and called it quits just a game later.

The outcome completed a bizarre first week for world number one Djokovic who was also champion in New York in 2011.

After labouring over four sets to beat Jerzy Janowicz on Monday, he was handed a walkover into the third round when Czech opponent Jiri Vesely withdrew from their second round clash with an arm injury.

"I have never had this happen before in my career, getting a walkover and the next match lasting just half an hour," said Djokovic who faces either John Isner of the United States or Britain's Kyle Edmund for a quarter-final slot.

"I wish Mikhail a speedy recovery. He said he carried the injury into the match."

The brief encounter for Djokovic had been preceded on Arthur Ashe Stadium by women's eighth seed Madison Keys pulling off an epic comeback to beat Japan's Naomi Osaka.

Keys won the latest-ever finishing women's match at the tournament on Monday when she completed victory over compatriot Alison Riske at 1:48am.

On Friday, the 21-year-old was involved in more drama when she rallied from 1-5 down in the final set to defeat Osaka 7-5, 4-6, 7-6 (7/3).

The 18-year-old Osaka was so traumatised by her failure to convert her dominance into victory that she broke down in tears as she twice tried and failed to serve for the victory.

"This is the greatest comeback of my career, hands down," said Keys who will face two-time runner-up Caroline Wozniacki for a quarter-final spot.

Jack Sock, the American 26th seed, reached the fourth round for the first time by knocking out 2014 champion Marin Cilic 6-4, 6-3, 6-3 in tie where he did not face a single break point.

The 23-year-old Sock, whose last two appearances at the US Open had ended in retirements, goes on to face French ninth seed Jo-Wilfried Tsonga.

Tsonga, a two-time quarter-finalist, made the last 16 with a 6-3, 6-4, 7-6 (7/4) victory over South Africa's Kevin Anderson.

Wozniacki, who knocked out ninth-seeded former champion Svetlana Kuznetsova in the second round, clinched a seventh win in seven meetings over unorthodox Monica Niculescu of Romania.

The Dane's 6-3, 6-1 victory featured eight breaks of serve.

Roberta Vinci, the Italian seventh seed and runner-up to compatriot Flavia Pennetta in 2015, overcame a second set blip to defeat 21-year-old Carina Witthoeft 6-0, 5-7, 6-3.

The 33-year-old Vinci led 5-4, 30-0 in the second set before her 84th-ranked German opponent dug deep to take the tie into a decider.

But Vinci prevailed on the back of 40 winners and will meet Lesia Tsurenko of the Ukraine for a quarter-final place.

Tsurenko, the world 99, made the last 16 at a Slam for the first time by beating 12th seed Dominika Cibulkova of Slovakia 3-6, 6-3, 6-4.

The 27-year-old Tsurenko committed 44 unforced errors. Fortunately for her, newly-married Cibulkova hit 54.

Latvia's Anastasija Sevastova backed up her shock victory over third seed and French Open champion Garbine Muguruza by making the last 16 for the first time with a 6-4, 6-1 win over Kateryna Bondarenko of the Ukraine.

World number 48 Sevastova, who briefly retired in 2013, has matched her best run at a Slam and next faces British 13th seed Johanna Konta who put out Belinda Bencic 6-2, 6-1.

Later Friday, Rafael Nadal, the 2010 and 2013 champion, takes a 3-0 lead over Andrey Kuznetsov of Russia into their night-time clash on Arthur Ashe Stadium.

German second seed and Australian Open champion Angelique Kerber closes the night session against American 17-year-old CiCi Bellis.