Former champion Andy Murray, given a wildcard as he continues to climb back from two hip surgeries, will face Japan's Yoshihito Nishioka in his first Grand Slam singles match since the 2019 Australian Open.
World number one Novak Djokovic will play Bosnia's Damir Dzumhur in his opening match at Flushing Meadows which will be held without fans this year because of the coronavirus pandemic.
The earliest seed he could meet would be a possible third-round clash with number 28 Jan-Lennard Struff who he beat easily at the Western & Southern Open in New York this week.
Dominic Thiem, seeded two in the absence of reigning champion Rafa Nadal, opens against Spaniard Jaume Munar.
Serena Williams, seeded three, plays compatriot Kristie Ahn in round one but a meeting with 2017 U.S. Open champion Sloane Stephens, seeded 26th, is likely in round three.
Williams, bidding to win her home slam for a seventh time, is also chasing a record-equalling 24th Grand Slam title having lost her last four major finals, including the past two years in New York.
Serbian Djokovic, who tested positive for Covid-19 after an exhibition event he organised in Croatia this year, is seeking an 18th Grand Slam title which would leave him just one behind Nadal and two short of Roger Federer who is out injured.
The highest seed he could face before the quarter-finals is number 16 John Isner in round four.
Djokovic has a perfect record this year, winning all 21 matches he has played.
Last year's runner-up Daniil Medvedev is seeded third and plays Argentina's Federico Delbonis in round one.
Fourth seed Stefanos Tsitsipas is up against Spain's Albert Ramos-Vinolas in round one but another young gun, fifth seed Alexander Zverev, has been handed a tough first hurdle with a match-up against big-serving Kevin Anderson who reached the final in 2017 and the Wimbledon final in 2018.
PLISKOVA FACES KALININA, OSAKA TO PLAY MUCHOVA
With six of the women's top 10 skipping the tournament, the Czech Republic's Karolina Pliskova is top seed and she begins her quest for her first Grand Slam title against Ukraine's Anhelina Kalinina.
Australian Open champion Sofia Kenin is seeded second and faces a tricky start against Belgium's Yanina Wickmayer.
Serena's unseeded sister Venus, playing in her 22nd U.S. Open at the age of 40, takes on 20th seed Karolina Muchova.
Former champion Naomi Osaka, who led a protest against racial injustice this week, plays fellow Japanese Misaki Doi.
Wildcard Kim Clijsters, who made a second comeback from retirement this year, plays 21st seed, Ekaterina Alexandrova.
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