Pironkova announced her return to tennis in March, just before the COVID-19 pandemic. She returned to action at the 2020 US Open, playing her first tournament since the 2017 Wimbledon Championships. She entered the tournament using a protected ranking of No. 123 that she applied for prior to the birth of her son. Pironkova began her campaign with a straight-sets win over world No. 120, Ludmilla Samsonova in the first round. She then followed it up with wins over 10th seed Garbiñe Muguruza and 18th seed Donna Vekić in the second and third rounds, respectively. Playing in just her second round of 16 match in New York, Pironkova defeated France's Alizé Cornet in a three-hour long match. In the quarterfinals, she was defeated by Serena Williams, 4–6, 6–3, 6–2, despite leading by a break in the second set. USOpen.org writer Steve Pratt highlighted Pironkova's run to the quarterfinals, noting how her successful return to tour after a three-year absence " the story of the women’s singles draw".