Top seed Jannik Sinner, whose doping case has dominated the lead-up to the US Open, faces a tough road to the New York final while in-form Aryna Sabalenka will also be tested, according to the draw released on Thursday.
Sinner won in Cincinnati this week to claim his fifth title of a breakout season before the revelation that he avoided a ban over two positive tests in March as it was ruled the Italian bore no fault or negligence for the violations.
The Australian Open champion is projected to face 14th seed Tommy Paul in the fourth round, 2021 winner Daniil Medvedev (5) in the quarterfinals, Carlos Alcaraz (3) in the semis and defending champion Novak Djokovic (2) in the final.
Djokovic, who has not competed since winning the gold medal at the Paris Olympics, will begin against a qualifier and is expected to meet Andrey Rublev in the quarterfinals and fourth seed Alexander Zverev in the semis.
Reigning French Open and Wimbledon champion Alcaraz, who lost the opening match of his only US Open tune-up event, will also start against a qualifier and could face Poland's Hubert Hurkacz in the quarterfinals.
Among the first-round matches to watch on the men's side is big-hitting Ben Shelton, who electrified the home crowds last year with a spirited run to the semis, against 2020 champion Dominic Thiem, who is retiring at the end of the year.
In the women's draw, top seed Iga Swiatek, a five-time Grand Slam winner who reached the fourth round last year, will start against a qualifier and faces a potential quarterfinal clash against Canadian Open champion and Cincinnati runner-up Jessica Pegula.
Second seed Sabalenka, looking to go one further after finishing runner-up in New York last year, returns well-rested after a mid-year break to focus on her health. She will be confident about her chances after winning in Cincinnati.
Sabalenka's fortnight may include a third-round date with Ekaterina Alexandrova (29) followed by a fourth-round clash with Madison Keys (14), Zheng Qinwen (7) in the quarters, defending champion Coco Gauff (3) in the semis and Swiatek in the final.
Gauff, who last year became the first American to win a US Open singles title since 2017, will begin her title defense against Frenchwoman Varvara Gracheva.
Among the more high-profile first-round women's matchups, four-time Grand Slam winner Naomi Osaka, in her first New York appearance since becoming a mother, will face Latvian 10th seed and former French Open champion Jelena Ostapenko.
Wimbledon and French Open runner-up Jasmine Paolini will face 2019 US Open champion Bianca Andreescu for a third consecutive Grand Slam.
The US Open will be played from August 26 to September 8.
