In March 2021, he won his first ATP title at the 2021 Qatar Open with Andrey Rublev in doubles. A week later, as a wildcard, Karatsev won his first ATP singles title at the 2021 Dubai Open, beating South African Lloyd Harris in the final. Karatsev, who was unseeded and beat four seeded players to reach the final, joined Wayne Ferreira (1995) and Thomas Muster (1997) in this achievement. As a result, he entered the top 30 of the ATP singles rankings for the first time in his career. On 24 April 2021, Karatsev defeated world No. 1 Novak Djokovic on his home court at the Serbia Open to reach the final. At the 2020 Summer Olympics, he won the silver medal with Elena Vesnina in mixed doubles.