Cerúndolo made his ATP main draw debut at the 2021 Córdoba Open where, as a qualifier, he won the title.

In August and September, he won his second and third Challengers in Como, Italy and Banja Luka, Bosnia and Herzegovina.

[7][8] In his Next Gen ATP finals debut, Cerúndolo lost to fourth seed Brandon Nakashima in his first match.

His third and final match ended in defeat to the tournament's top seed and eventual champion Carlos Alcaraz.

[9][10][11] Cerúndolo made his Grand Slam debut at the 2022 Australian Open as a direct entry into the main draw where he lost to qualifier Tomáš Macháč.

[12] He did not play in any of the ATP tournaments on clay due to leg and hip injuries and as result dropped out of the top 130 to No.

[13] In Córdoba, Argentina he received a wildcard and defeated fellow Argentine and top seed Diego Schwartzman to reach the quarterfinals.

Cerúndolo recorded his first Major win on his debut at the US Open defeating Ilya Ivashka in five sets.