[4] Mannarino made his Grand Slam singles debut at the 2007 French Open, where as a wildcard, he lost in the first qualifying round to Marin Čilić in straight sets.

Mannarino received a wildcard for the singles main draw of his home Grand Slam tournament, the 2008 French Open, where he lost to Argentine qualifier Diego Junqueira in the first round in straight sets.

Mannarino played at the 2008 Open de Moselle in France, entering the singles main draw as a qualifier; he reached the semifinals, defeating sixth seed Andreas Seppi in the first round, Rik de Voest in the second round, Marc Gicquel in the quarterfinals, before losing to Paul-Henri Mathieu in the semifinals in two tiebreaks.

In November 2008, he played in an ATP Challenger Tour tournament in Jersey, where, seeded fourth, he won the singles event, defeating Andreas Beck in two tiebreaks in the final.

[5] He participated in the inaugural Masters France in December 2008, an exhibition tournament, along with a number of top French players, but lost his three round-robin matches in straight sets to Paul-Henri Mathieu, Michaël Llodra and Arnaud Clément.

He received a main draw singles wildcard for the 2009 Australian Open, where he lost to 14th seed Fernando Verdasco in the first round.

In 2011, he lost in the main draw singles second round of the Australian Open and Wimbledon, falling to six-time champion Roger Federer in the latter in straight sets.

He and his partner Juan Sebastián Cabal were defeated in the quarterfinals by the Indian-Romanian pair and eventual champions Rohan Bopanna and Florin Mergea.

He reached his first career ATP World Tour Masters 1000 singles quarterfinal at the 2017 Rogers Cup, where he upset no.

[8] In October, Mannarino reached his third ATP World Tour singles semifinal of 2017 at the Kremlin Cup, where he lost to Ričardas Berankis.

[11] In the first week of February, the second-seeded Mannarino was upset by the unseeded Marcos Baghdatis in three sets in the second round of the Sofia Open.

One week later, the fourth-seeded Mannarino lost in the semifinals of the New York Open to the second seed Sam Querrey in three tight sets.

Mannarino lost before the quarterfinal round of the singles main draw of his next four ATP World Tour tournaments in Acapulco, Indian Wells, Miami and Monte-Carlo.

[35] Seeded second and two-time finalist at the Antalya Open, he reached the quarterfinals where he was beaten by eventual champion Lorenzo Sonego.

[59] Competing in Acapulco, he failed to convert match points in the third set and was eventually eliminated by the seventh seed and 2014 champion, Grigor Dimitrov, in their second round three-set thriller.

[70] In Paris, he made it to the third round where he fell in a tight three-set match to fourth seed and eventual finalist, Alexander Zverev.

[71] Playing his final tournament of the season at the Sofia Open, he reached the semifinal where he lost to Jannik Sinner, who would end up winning the title.

[87] Seeded seventh at the Stuttgart Open, his first grass-court tournament of the season, Mannarino fell in the first round to qualifier James Duckworth.

[90] He advanced to the quarterfinals when his opponent, second seed Dominic Thiem, retired during their second round encounter due to a right wrist injury.

[92] At Wimbledon, he retired during his first-round match against eight-time champion and former World Number 1, Roger Federer, due to slipping behind the baseline and injuring his right knee.

At the 2022 Atlanta Open he reached his fifth quarterfinal of the season as a lucky loser defeating Peter Gojowczyk and debutant wildcard American Andres Martin (tennis).

[109][110] At the 2022 Astana Open he reached his seventh quarterfinal of the season defeating Stan Wawrinka,[111][112] and lucky loser David Goffin.

[113] At the same tournament he also reached his maiden doubles final with compatriot Fabrice Martin defeating top seedsTim Pütz/Michael Venus (tennis), and Polish duo Hubert Hurkacz/Jan Zieliński in the semifinals.

At the next tournament, the 2023 Queen's Club Championships he defeated third seed Taylor Fritz also in the second round for his tenth Top 10 win.

In July, Mannarino won his third title at the 2023 Hall of Fame Open in Newport, defeating Alex Michelsen in the final.

[143] He reached his fifteenth final defeating seventh seed Sebastian Ofner[144] and Pavel Kotov[145] and returned to his career-high ranking of No.

[147][148] At the 2024 Australian Open, he reached his second fourth round at this Major defeating 16th seed Ben Shelton,[149] before losing to world No.

[citation needed] He defeated James Duckworth to reach the semifinals at the Dallas Open[151] where he lost to Marcos Giron.

[152] Mannarino reached the quarterfinals at the Chengdu Open with a wins over qualifier Terence Atmane[153] and wildcard Zhou Li,[154] before losing in the last four to top seed Lorenzo Musetti.

Only main-draw results in ATP Tour, Grand Slam tournaments, Davis Cup/ATP Cup/Laver Cup and Olympic Games are included in win–loss records.