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.
@DjokerNole's road to a fourth #USOpen title
— US Open Tennis (@usopen) August 26, 2021
Round 1: Qualifier
Round 2: Struff
Round 3: Goffin
Round 4: De Minaur
Quarterfinals: Berrettini
Semifinals: Zverev
Final: Medvedev pic.twitter.com/9Rtq4lPfwQ
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.
@ashbarty's route to a third Grand Slam singles title
— US Open Tennis (@usopen) August 26, 2021
Round 1: Zvonareva
Round 2: Tauson
Round 3: Kudermetova
Round 4: Brady
Quarterfinals: Swiatek
Semifinals: Pliskova
Final: Sabalenka#USOpen pic.twitter.com/eDo907HpX4