Second seed Angelique Kerber enjoyed a stress-free passage into the US Open second round after her opponent Polona Hercog retired injured.
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Djokovic, who has struggled with a wrist injury, won 6-3 5-7 6-2 6-1 after calling the trainer in the first set.
Novak Djokovic opened defence of his US Open title with a laboured 6-3, 5-7, 6-2, 6-1 win over Poland’s Jerzy Janowicz on Monday that brought new concerns about the world number one’s fitness.
“To be one day number one, I think this is a goal from everybody, especially also for me”, said Kerber.
The defending champion began the second set serving at below 90mph but Janowicz was too inconsistent to take advantage, and Djokovic eventually ran out a comfortable victor – at least in terms of the scoreline.
French 13th seed Richard Gasquet, a semi-finalist three years ago, was the day’s biggest casualty.
Two-time grand slam victor and ninth seed Svetlana Kuznetsov beat former French Open victor Francesca Schiavone of Italy 6-1 6-2, while double Wimbledon champion Petra Kvitova, the number 14, started with a defeat of Latvian Jelena Ostapenko 7-5 6-3.
The injury concerns, combined with the absence for the first time since 1999 of five-time victor Roger Federer, have put 2012 champion Andy Murray in the position of favourite.
The Spaniard’s reward for a fifth win in five meetings against the Russian-born player is a match-up with Italian veteran Andreas Seppi. Nadal closes the daytime session on Ashe while Djokovic starts the evening entertainment.
Last year’s finalist in New York, Roberta Vinci, beat Germany’s Anna-Lena Friedsam 6-2 6-4.
Williams is chasing a record seventh US Open and will equal Steffi Graf’s record of 186 successive weeks at world number one.
A year ago oddsmakers had set the unseeded Vinci as a 300-1 longshot to win the season’s final grand slam and the tale of the tape offered no hints of possible upset. Gasquet, who has reached the last 16 at Flushing Meadows four times in his career, was outplayed throughout and his US Open stay lasted just one hour, 41 minutes.
“I did nothing to deserve to win that set”. “But I will not put too much pressure on myself. because I know that when I put the pressure (on), I’m not playing my tennis then”. “My best memories come from here in 2014”.
“I’m really trying to focus on my game, step by step”.
A wildly uneven display from both men saw Janowicz level at one set all after Djokovic double-faulted and blazed a forehand wide, shaking his right arm in apparent discomfort.
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After a sizzling start to the season that included grand slam wins number 11 and 12 at the Australian and French Opens, Djokovic has seen a shocking drop in form with a third-round loss at Wimbledon followed by a first-round exit at the Rio Olympics.
