The world No. 1 was taken to four sets by 247th-ranked Pole Jerzy Janowicz in his first tournament since losing his first singles match at this month’s Rio Olympics.
Djokovic admitted before the season’s final grand slam that his injured wrist has not fully healed, and Monday he had to call for a trainer in the first set to treat his right arm.
“Calling for the medical timeout was just prevention,” the 29-year-old told reporters. “It’s all good; to be honest, I take it day by day.”
“It’s getting better and better each day. I’m glad that I’m experiencing that so hopefully, as the tournament progresses, I’ll reach my peak.”
The Serb will face Jiri Vesely in the second round on Wednesday. The 49th-ranked Czech beat India’s Saketh Myneni in five sets.
Fourth seed Rafael Nadal continued his recent promising run of form by beating Denis Istomin of Uzbekistan in three sets, dropping only seven games in the process.
The Spaniard has been troubled by a battery of ailments over the past two years. A wrist injury forced him to withdraw from the French Open and kept him out of Wimbledon.
However, Nadal bounced back at the Olympics, winning a gold medal with doubles partner Marc Lopez and reaching the bronze medal match, which he lost to Kei Nishikori.
The two-time US Open champion will next play Italy’s Andreas Seppi.
Raonic and McEnroe end coaching ties
Fifth seed Milos Raonic beat German Dustin Brown in straight sets, following a surprise announcement that his coaching tie with John McEnroe had ended.
McEnroe cited his various media commitments as being a hindrance to his coaching duties with 25-year-old Canadian at Wimbledon, despite the world No. 6 making it all the way to his first grand slam final.
McEnroe indicated that their parting was by mutual consent, and left the door open to the pair working together in the future.
“It’s best to sort of separate at this stage,” McEnroe told ESPN, one of his employers. “It will just make life easier for everyone.”
Raonic, who will next play American Ryan Harrison, told reporters: “It’s a decision we’re both okay with. We spoke about it, were up front, and there’s no ill feelings over it.”
Tiafoe shines in grand slam debut
Teenage wildcard entry Frances Tiafoe tested compatriot John Isner, racing to a two-set lead before the long-standing US No. 1 battled back to triumph in a fifth-set tiebreak.
As temperatures reached into the 90s in New York, the six-foot 10-inch Isner needed 35 aces to defeat the 18-year-old from Maryland, who failed to serve out for the match in the final set.
“At such a young age, he seems to be the type of kid that can rise up to the big occasion, big moment, and great atmosphere,” Isner told reporters of the 2015 US national junior champion. “I can’t say enough about Frances. He has a fantastic future.
“He’s got wheels; he’s got the hands; he’s got shots on both sides. One area, if he improves his second serve a little bit. But I would certainly buy stock in him right now, for sure.”
Isner, the 20th seed, next faces Belgium’s Steve Darcis as he seeks to build on last year’s fourth-round appearance. The 31-year-old has never got past the quarterfinals in nine attempts at his home slam.
Last year’s surprise finalist in the women’s tournament, Roberta Vinci, sailed past her first-round opponent Anna-Lena Friedsam of Germany 6-2 6-4.
The Italian seventh seed, who ended Serena Williams’ bid to complete her first career grand slam in the semifinals before losing to compatriot Flavia Pennetta, will next play American Christina McHale.
French Open winner Garbiñe Muguruza of Spain took three sets to beat Belgian Elise Mertens. The third seed, who lost in round two last year, next faces 48th-ranked Latvian Anastasija Sevastova.
Second seed Angelique Kerber, the silver medalist in Rio, had easy progress into round two after Slovenian opponent Polona Hercog retired while trailing 6-0 1-0.
The German, who can replace Williams as world No. 1 by winning the title at Flushing Meadows, will next play Croatian veteran Mirjana Lucic-Baroni — who made her grand slam debut here as a 15-year-old in 1997.
Serena Williams, who has been battling a shoulder injury, will play Russian Ekaterina Makarova Tuesday as she begins her bid for an Open-Era record 23rd grand slam title.
Her sixth-seeded older sister Venus Williams is up against Ukraine’s Kateryna Koslova.
Polish fourth seed Agnieszka Radwanska and Romania’s No. 5 Simona Halep are also in action, against American Jessica Pegula and Belgium’s Kirsten Flipkens respectively.
Olympic men’s champion Andy Murray plays Czech Lukas Rosol, third seed Stan Wawrinka begins against Spain’s Fenrando Verdasco, world No. 7 Nishikori takes on Benjamin Becker of Germany, while Olympic men’s singles runner-up Del Potro faces fellow Argentine Diego Schwartzman.