2022. The following month, Rune made his main draw debut at the French Open, where he shocked 14th seed Denis Shapovalov in the first round before defeating Henri Laaksonen and Gaston in the second and third rounds, respectively, all in straight sets. He then stunned fourth seed Stefanos Tsitsipas to earn his third win of the season over a top 15 player to reach his first career Grand Slam quarterfinal, making him the first Danish man in singles to reach the quarterfinals of any Grand Slam tournament in the Open Era. There, he succumbed to Casper Ruud in four sets, but the achievement landed Rune inside the world's top 30. Rune did not win a match between the French Open and Washington. In Washington, as the 9th seed, he beat Benoît Paire in the second round before losing to wildcard J.J. Wolf in the third round. In Montreal, Rune beat Fabio Fognini in straight sets in the first round, then lost to eventual champion Pablo Carreño Busta in the second round. In Cincinnati, Rune lost to 9th seed Cameron Norrie in the first round. At the US Open, Rune beat Peter Gojowczyk and received a walkover from John Isner to reach the third round, where he lost again to Norrie. He reached his second ATP final in Sofia, beating Tim van Rijthoven, Lorenzo Sonego and Ilya Ivashka, then moved on to the final after defending champion and top seed Jannik Sinner retired in the middle of their match due to injury. He lost to Marc-Andrea Hüsler in the final. As a result he qualified for the 2022 Next Generation ATP Finals in Milan on 30 September. He reached his third final at the 2022 Stockholm Open by defeating fifth seed Alex de Minaur. As a result he reached the top 25 in the rankings on 24 October 2022. He won his second title defeating top seed Stefanos Tsitsipas in the final. The following week at the next tournament in Basel he beat again seventh seeded Alex de Minaur in the first round. He reached the final defeating two Frenchmen Ugo Humbert and Arthur Rinderknech, and then sixth seed Roberto Bautista Agut in the semifinals. As a result he made his top 20 debut in the rankings at No. 18 on 31 October 2022. He became only the fourth man born in the 2000s to reach the Top 20 in the