De Minaur started his 2021 season at the Antalya Open. Seeded fourth, he won his fourth ATP singles title when his opponent, eighth seed Alexander Bublik, retired from the final due to a right ankle injury. Playing for Australia at the 2021 ATP Cup, de Minaur lost both of his matches to Roberto Bautista Agut, and Stefanos Tsitsipas. Seeded 21st at the Australian Open, de Minaur reached the third round where he was defeated by 16th seed Fabio Fognini.