The Serb, who has been struggling with a wrist injury in recent weeks, dropped the second set before coming through 6-3, 5-7, 6-2, 6-1.
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The American superstar, seeking a record seventh US Open title, next faces Kazakhstan’s Yaroslava Shvedova, a 6-2, 7-5 victor over China’s Zhang Shuai.
While Djokovic and Nadal are contemplating fourth round matches, there was no such joy for former champion Marin Cilic, who was bounced out of the tournament by Jack Sock.
Novak Djokovic, of Serbia, motions after Mikhail Youzhny, of Russian Federation, retired from their match in the first set during the third round of the U.S. Open tennis tournament, Friday, Sept. 2, 2016, in NY.
And then Djokovic only contested six games Friday, until his third-round opponent, Mikhail Youzhny, stopped because of a strained left hamstring, prompting the 12-time major champion to head back out on court with coach Boris Becker for a practice session.
The outcome completed a freakish first week for World No. 1 Djokovic.
Jiri Vesely of the Czech Republic didn’t even make it out to the court, withdrawing before their second-round match on Wednesday because of an injured arm.
While one American impressed, there was not much joy for another as John Isner, the No.20 seed, was beaten by the impressive Kyle Edmund of Great Britain 6-4, 3-6, 6-2, 7-6 (7-5).
A disgruntled Arthur Ashe Stadium crowd got a consolation prize though.
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.
Djokovic’s win over Youzhny was his seventh win over the Russian, in their first meeting since the quarterfinal of the US Open in 2013.
KEYS VS. WOZNIACKI: There will be a matchup of vastly contrasting styles when No. 8 Madison Keys takes on two-time runner-up Caroline Wozniacki in the afternoon on Ashe.
The 23-year-old, whose last two appearances at the US Open had ended in retirements, goes on to face French ninth seed Jo-Wilfried Tsonga (who got past Kevin Anderson in four sets).
He has started strongly and looks a serious threat with wins over Martin Klizan 6-2, 6-1, 6-1 and Guido Pella 6-2, 6-1, 7-3 he may cause a massive upset.
Williams advanced to the third round as well, picking up her second consecutive 6-3, 6-3 victory in the second round.
Djokovic now has more time to recuperate ahead of attempting to book a place in the quarter-finals.
Monfils produced the straightest of faces when asked if he agreed with recent comments made by Tillstrom that the Frenchman could win a grand slam and qualify for the ATP World Tour Finals in London. The 27-year-old Tsurenko committed 44 unforced errors.
Kerber had an easy ride in the first round when her Slovenian opponent Polona Hercog retired at 6-0 1-0 in the German’s favor. Fortunately for her, Cibulkova hit 54.
Fourth-round first-timer Anastasija Sevastova, who put out French Open champion Garbine Muguruza in the second round, meets British 13th seed Johanna Konta.
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No. 1 Novak Djokovic def. Mikhail Youzhny, 4-2 (ret.) No. 4 Rafael Nadal def. Andrey Kuznetsov, 6-1, 6-4, 6-2 No. 26 Jack Sock def.
