Seeds The following were the seeded players. Seedings were based on ATP rankings as of August 9, 2021. Rank and points before were as of August 16, 2021. For the first time since the ATP Tour resumed from its pandemic suspension in August 2020, ATP rankings points were added and dropped per traditional methodology beginning 23 August 2021 (the rankings after the 2021 Western & Southern Open in Cincinnati). A player's current Western & Southern Open ATP ranking points (the greater from 2019 and 2020) dropped 23 August 2021 and were replaced with points earned by the player at this year's Western & Southern Open. Those new points would stay on a player's breakdown for 52 weeks, dropping 22 August 2022. Players who had Western & Southern Open points in their breakdown and did not compete in this year's event also had their existing Cincinnati ranking points drop on 23 August 2021. † The player is also defending points from the
2019 Winston-Salem Open, which was played during this calendar week in 2019. ‡ The player did not qualify for the tournament in 2019 or 2020. Accordingly, points for his 19th best result are deducted instead. ^ Because the 2021 tournament was non-mandatory, the player substituted his 19th best result in place of the points won in this tournament.
Other entrants The following players received
wild cards into the main singles draw: •
Mackenzie McDonald •
Andy Murray •
Brandon Nakashima → replaced by
Federico Delbonis •
Adrian Mannarino → replaced by
Miomir Kecmanović •
John Millman → replaced by
Dominik Koepfer •
Rafael Nadal → replaced by
Guido Pella •
Kei Nishikori → replaced by
Laslo Đere •
Milos Raonic → replaced by
Benoît Paire •
Dominic Thiem → replaced by
Dominik Koepfer •
Stan Wawrinka → replaced by
Dušan Lajović ==ATP doubles main-draw entrants==