Berrettini's strong performance advanced Italy to the final of the 2021 ATP Cup against Russia, where he lost to Daniil Medvedev in two sets. At the 2021 Australian Open he reached the fourth round but withdrew from the tournament with abdominal pain. He remained out of competition until the clay season in April. He won his first singles title in over a year at the Serbia Open, over Aslan Karatsev.