See main article: article and 2021 Winston-Salem Open.
Łukasz Kubot and Marcelo Melo were the reigning champions from when the tournament was last held in 2019, but lost in the semifinals to Ivan Dodig and Austin Krajicek.
Marcelo Arévalo and Matwé Middelkoop won the title, defeating Dodig and Krajicek in the final, 6–7(5–7), 7–5, [10–6].