- Defending champion Carlos Alcaraz will open his US Open campaign against Russia's Roman Safiullin, who made the fourth round of Wimbledon, marking the second seed's first competitive singles match since suffering a right wrist injury in April.
- Top seed Alexander Zverev, who leads the men's draw following Jannik Sinner's knee injury withdrawal, faces Italy's Lorenzo Sonego, whilst two-time defending women's champion Aryna Sabalenka begins against Camila Osorio.
- Venus Williams has been drawn against 2020 Australian Open champion Sofia Kenin in the first round after Serena Williams decided to focus exclusively on doubles, allowing Kenin to receive the final wildcard.
- Notable opening-round ties in the men's singles include Cincinnati Open winner Arthur Fils against Stefanos Tsitsipas, and former champion Stan Wawrinka taking on Matteo Berrettini in his final Grand Slam appearance.
- Potential women's quarter-final matchups could feature Aryna Sabalenka against Linda Noskova, Elena Rybakina versus Iga Swiatek, Jessica Pegula against Karolina Muchova, and Coco Gauff taking on Mirra Andreeva.
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