Andy Murray will play Australia's James Duckworth when he makes his return to Grand Slam tennis after a 14-month absence with a hip injury.
The former world number one, now ranked 378th, could play third seed Juan Martin del Potro in the third round.
Kyle Edmund, his replacement as British number one, faces Italy's Paolo Lorenzi, while Cameron Norrie meets Australian Jordan Thompson.
Johanna Konta has a tough match against French sixth seed Caroline Garcia.
British number one Konta, 27, has dropped to 46 in the rankings after a year in which she has struggled to find consistency.
Heather Watson and Katie Swan face each other in qualifying on Friday for a place in the main draw, but Naomi Broady is out, as is brother Liam in the men's draw.
The US Open, the fourth and final major of the year, begins in New York on Monday.
Murray avoids major names
Murray, 31, is set to return to five-set matches at Flushing Meadows - the scene of the first of his three Slam triumphs in 2012 - after pulling out of this year's Wimbledon on the eve of the tournament.
Duckworth, himself coming back from a catalogue of injuries which sidelined him for a year, is ranked 445th in the world.
Murray decided he was not ready to compete in five-set matches last month, instead preferring to train on the American hard courts in preparation for the US Open.
The Scot had surgery in January to rectify a long-standing hip injury which had kept him out of competitive action since his defeat by Sam Querrey in the Wimbledon quarter-finals in July 2017.
An 11-month absence from the ATP Tour ended with a three-set defeat by Australian Nick Kyrgios at Queen's in June and he has since played three other tournaments - Eastbourne in the run-up to Wimbledon, followed by Washington and Cincinnati this month.
Murray won three matches in Washington before pulling out of his quarter-final, then lost in the opening round at Cincinnati to France's world number 17 Lucas Pouille.
Murray has direct entry into the main draw at Flushing Meadows because of his protected ranking.
If the unseeded Briton beats Duckworth, he will face a Spaniard in either Feliciano Lopez or 30th seed Fernando Verdasco before a potential third-round match against Argentina's 2009 US Open champion Del Potro.
Federer and Djokovic drawn in same quarter
World number one Rafael Nadal plays fellow Spaniard David Ferrer in the opening match of his title defence, while second seed Roger Federer meets Japan's Yoshihito Nishioka in a first contest between the pair.
Nadal, 32, and Federer, 37, cannot meet until the final - if they get that far - in what would be their first encounter at Flushing Meadows.
Federer could face Novak Djokovic, who is looking to move level with Pete Sampras on 14 Slam triumphs, in the quarter-finals.
Djokovic, who beat the Swiss in the Cincinnati Open final last week, will play Marton Fucsovics of Hungary in the first round.
Bulgarian eighth seed Grigor Dimitrov faces three-time Slam champion Stan Wawrinka, who is a wildcard as he continues to rebuild his career after injury, in the first round - a repeat of their Wimbledon opener this year, which the Swiss won.
Williams sisters could meet in third round
Serena Williams, 36, is seeded 17th as she continues to make her comeback after giving birth last September - and could meet older sister Venus, seeded 16th, in the third round.
One of the Williams sisters could then face world number one Simona Halep, who plays Estonia's Kaia Kanepi, in the last 16.
Serena Williams, who is bidding for her seventh US Open title, plays Poland's world number 60 Magda Linette in her opener.
Defending women's champion Sloane Stephens starts her defence against Evgeniya Rodina, with two-time Grand Slam winner Victoria Azarenka potentially awaiting her in the third round.