[3] Cerúndolo made his main draw debut in a Grand Slam at the 2021 French Open as a lucky loser, where he lost to Thiago Monteiro.

There, he beat Benoît Paire, Roberto Carballés Baena and again Kecmanović to reach his first ATP 500 semifinal, where he lost in straight sets to Diego Schwartzman.

Cerúndolo recorded his first ATP Tour victories on a hard court at the Masters 1000 event in Miami, defeating Tallon Griekspoor and seeded players Reilly Opelka and Gaël Monfils en route to the fourth round.

103 at the time, he became the lowest-ranked semifinalist in the history of the Miami Open, and also became the first male player since Jerzy Janowicz in 2012 to reach the semifinals on their Masters 1000 level debut.

In Båstad, Cerúndolo recorded his first win against a player inside the Top-10 after beating top seed and defending champion Casper Ruud in 3 sets.

He represented Argentina for the first time in the Davis Cup finals, where he lost both matches to Jannik Sinner and Borna Ćorić respectively.

[11][12] Cerúndolo won his two first matches at a Grand Slam at the Australian Open after beating Guido Pella and Corentin Moutet to reach the third round on his debut at this Major.

[13] In Córdoba, Argentina he defeated fellow Argentine Federico Delbonis to reach the quarterfinals but lost to eventual runner-up compatriot Federico Coria, however, his brother Juanma defeated Diego Schwartzman in the same tournament, as a result, Francisco he became Argentine No.

6 Félix Auger-Aliassime and getting his revenge for his third round loss at the 2023 BNP Paribas Open two weeks earlier.

In Rome he reached his second Masters quarterfinal of the season defeating Wu Yibing, Grégoire Barrère and world No.

[17] In Lyon he reached a new ATP Tour final, beating Juan Pablo Varillas, Jack Draper, and Cameron Norrie, in the title match he lost against Arthur Fils in straight sets.

He reached the round of 16 for the first time at a Major defeating ninth seed Taylor Fritz, his fourth top-10 win of the season.

In Eastbourne he became the third Argentinian champion on grass after Guillermo Vilas and Javier Frana, and the first since 1995, defeating Marc-Andrea Hüsler, Zhang Zhizhen, Mackenzie McDonald and second seed Tommy Paul, beating both Americans in the same day.

On his return to clay at Båstad, he started his title defense beating Luca Van Assche in the second round, Federico Coria in the quarterfinals, but lost in the semifinals to eventual champion Andrey Rublev.

[22] On his debut at the Laver Cup he recorded the first ever win for South America at the event against Alejandro Davidovich Fokina.

[27] He reached his fifth ATP final at the 2024 Croatia Open Umag defeating Lorenzo Sonego and upsetting top seed Andrey Rublev.

[32][33] At the 2024 Rolex Paris Masters Cerundolo again upset sixth seed Andrey Rublev in straight sets with two tiebreaks recording his 100th tour-level win.