retired during his first-round encounter against fifth seed Grigor Dimitrov. Seeded 25th at the Miami Open, he was defeated in the third round by fifth seed Diego Schwartzman. Starting the clay-court season at the Monte-Carlo Masters, Mannarino lost in the first round to qualifier Federico Delbonis. Seeded 17th at the Barcelona Open, he was eliminated in the second round by Albert Ramos Viñolas. In Madrid, he was beaten in the first round by Spanish wildcard Carlos Alcaraz. At the Italian Open, he was defeated in round one by qualifier Hugo Dellien. In doubles, he and Benoît Paire reached the quarterfinals where they lost to second seeds and eventual champions, Nikola Mektić/Mate Pavić. Seeded eighth at the Geneva Open, he was beaten in the first round by compatriot, Arthur Cazaux. Seeded fourth at the Belgrade Open, he lost in the second round to Fernando Verdasco. At the French Open, he was defeated in his first-round match by Aljaž Bedene. Seeded seventh at the Stuttgart Open, his first grass-court tournament of the season, Mannarino fell in the first round to qualifier James Duckworth. Competing at the Queen's Club Championships in London, he was eliminated in the second round by sixth seed Dan Evans. At the first edition of the Mallorca Open, he won his first-round match over Jan-Lennard Struff. He advanced to the quarterfinals when his opponent, second seed Dominic Thiem, retired during their second round encounter due to a right wrist injury. He ended up getting beaten in his semifinal match by Sam Querrey. 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. Mannarino returned in August at the US Open. He lost in the second round to third seed Stefanos Tsitsipas. Seeded sixth in Sofia, Mannarino was defeated in the first round by Gianluca Mager. At the Indian Wells Masters, he fell in his first-round match to Andy Murray. After Indian Wells, he competed at the Kremlin Cup. He stunned top seed Andrey Rublev in the second round in a rematch of the 2019 final. He ended up losing in his quarterfinals match to lucky loser Ričardas Berankis. At the St. Petersburg Open, he was defeated in the first round by sixth seed Karen Khachanov. In Paris, he won his first-round match over Nikoloz Basilashvili. He lost in the second