Novak Djokovic, well rested after not playing since Monday, resumes his US Open title defence Friday against fiery Russian Mikhail Youzhny, a two-time semi-finalist in New York, for a last-16 place.
World number one Djokovic claimed a laboured win over Poland's Jerzy Janowicz in his opening match in which he required treatment on his right upper arm.
Fortunately for the two-time champion, he was able to rest up for the rest of the week after scheduled second round opponent Jiri Vesely handed him a walkover into the third round.
Youzhny, 34, and nicknamed 'Colonel' by his fans, made the last-four in New York in 2006 and 2010 and is ranked at 61 in the world having been as high as eight in 2008.
The eccentric Russian is also unusual in that he has a PhD in tennis studies.
Despite his academic skills, Youzhny will start as the underdog against Djokovic against whom he has a 3-6 losing record with his last win coming six years ago.
However, he did take a set off the Serb in the US Open quarter-finals in 2013.
Nadal, like Djokovic a two-time champion in New York, takes a 3-0 lead over Andrey Kuznetsov of Russia into their night-time clash on Arthur Ashe Stadium.
Two of those meetings came this year in Doha and Madrid but Nadal will not under-estimate the world number 47 especially as he still feels his way back from the wrist injury which sidelined him from the middle of Roland Garros to the Olympics.
Play on Ashe starts with two-time runner-up Caroline Wozniacki, who put out ninth seed and former champion Svetlana Kuznetsova in the second round, against Romania's Monica Niculescu.
That's followed by American eighth seed Madison Keys against Naomi Osaka of Japan.
German second seed and Australian Open champion Angelique Kerber closes the night session against American 17-year-old CiCi Bellis, the youngest player left in the women's draw.
Elsewhere, the tussle for last-16 spots sees 2014 champion Marin Cilic facing America's Jack Sock.
American number one John Isner meets British outsider Kyle Edmund.
French entertainers Jo-Wilfried Tsonga and Gael Monfils are on Grandstand.
Tsonga, the ninth seed, faces Kevin Anderson of South Africa while 10th-seeded Monfils, who turned 30 on Thursday, tackles Spain's Nicolas Almagro.
Roberta Vinci, the Italian seventh seed and 2015 runner-up, takes on Germany's Carina Witthoeft while double Wimbledon champion Petra Kvitova faces Elina Svitolina.