Stefanos Tsitsipas faces Andy Murray and Ash Barty will take on 2010 finalist Vera Zvonareva in the first round of the US Open.
French Open runner-up Tsitsipas and 2012 champion Murray is one of the standout matches in the opening round at Flushing Meadows.
Top seed Novak Djokovic will start his quest for a calendar Grand Slam against a qualifier in New York and could face a repeat of the Wimbledon final versus Matteo Berrettini in the last eight.
World number one Djokovic, a strong favourite for a record 21st major title with Rafael Nadal and Roger Federer absent due to injury, could do battle with Alexander Zverev at the semi-final stage.
Daniil Medvedev, the second seed, is in the bottom half with Tsitsipas, who he could come up against in the semi-final. Medvedev's first test will come against Frenchman Richard Gasquet.
Barty could come up against Iga Swiatek in the last eight and Karolina Pliskova if she makes it through to the semi-finals.
Simona Halep's encounter with Camila Giorgi is a mouthwatering first-round match, while defending champion Naomi Osaka returns to grand slam action against former US Open junior champion Marie Bouzkova.
Angelique Kerber could be a tough fourth round opponent for Osaka. Close friends Madison Keys and Sloane Stephens meet in another eye-catching first-round match.
There will be no Serena or Venus Williams at the final major of the year due to injuries.
Gauff sets up Swiatek semi-final meeting after downing Zheng in Rome
Coco Gauff will have the chance to down world number one Iga Swiatek after progressing to the Italian Open semi-finals with Tuesday's victory over Qinwen Zheng.
The 20-year-old breezed into the last-four draw in Rome after her straight-sets victory over Zheng, winning 7-6 (7-4) 6-1.
Gauff faced just one break point throughout the match, failing to hold her serve at 5-3 up as seven-seed Zhen battled back in the first set.
Yet Gauff eased through the tie-break and never looked back from there on, teeing up a meeting with Swiatek, who overcame Madison Keys in straight sets in her quarter-final clash.
Data Debrief: Young Gauff powers on
No player has won more matches than Gauff (61) in WTA-1000 events before turning 21, since the introduction of the format in 2009, as the American moved past Caroline Wozniacki (60) with victory here.
Wozniacki (eight) is also the only player to manage more WTA-1000 semi-final appearances before her 21th birthday, with Gauff's last-four qualification here taking her onto six – one ahead of Swiatek.
Medvedev's Italian Open title defence ended by Paul in Rome
Tommy Paul stunned defending champion Daniil Medvedev at the Italian Open on Tuesday.
Paul needed just one hour and 13 minutes to down Medvedev 6-1 6-4 to secure his first victory over a top-20 opponent and reach the quarter-finals.
Medvedev could not get going from the start, and was broken in all three of his service games in the opening set as Paul cruised into the lead.
And even after a brief resurgence at the start of the second set, Medvedev could not prevent his opponent from reeling off four successive games to pave the way for a memorable win.
Paul, who is into his first ATP Masters 1000 quarter-final on clay, will face Hubert Hurkacz for a place in the last four.
Data Debrief: Zverev brings up 10th Masters QF
While Medvedev crashed out, Alexander Zverev had no such trouble, as he claimed a straight sets win over Nuno Borges.
Zverev has now equalled Michael Chang in 10th place for the most quarter-finals made (28) in ATP Masters 1000 events since the format's introduction in 1990.
Former US Open champion Thiem misses out on Roland Garros wild-card invitation
Former US Open champion Dominic Thiem will have to fight for his place at the French Open after missing out on Tuesday's wild-card invitations.
Thiem will retire later this year due to a persistent wrist injury that has derailed his career but will likely need to battle through the qualifying rounds to appear at Roland Garros for a final time.
The two-time French Open semi-finalist is currently six places away from a main-draw spot for the upcoming major, with Richard Gasquet among the eight male players to secure a wild-card invitation.
Frenchman Gasquet will equal Feliciano Lopez's 21 tournaments at Roland Garros, the joint-most appearances of any player in the Open Era.
In the women's tournament, world number 99 Alize Cornet was also invited on a wild-card pick and will appear in a women's singles grand slam main draw for the 72nd time in her career.
That is the third most in the Open Era for major appearances, behind only Venus Williams (93) and Serena Williams (81).
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