[3] He competed in a handful of matches in 2010 and 2011, before taking a year out to finish his degree at Louisiana State University, where he studied sports administration as well as playing college tennis.

At the 2013 Kremlin Cup the Skupski brothers entered their first ATP World Tour tournament, progressing to the final, where they lost on a tie-break.

At the 2017 Wimbledon Championships he reached the quarterfinals as a wildcard for the first time in his career partnering with his brother Ken where they were defeated by 4th seeded pair Łukasz Kubot and Marcelo Melo.

Skupski and Spanish partner María José Martínez Sánchez were defeated in their mixed doubles semifinal at the 2019 Australian Open by third seeded pair and eventual champions Barbora Krejčíková and Rajeev Ram.

[11] With Murray he reached his first Grand Slam semifinal at the 2019 US Open (tennis) where they lost to the top-seeded Colombian pair and eventual champions Juan Sebastián Cabal and Robert Farah.

He made his first Masters 1000 final at the 2020 Western & Southern Open defeating top seeded pair Cabal/Farah in the first round en route before losing to Pablo Carreno Busta and Alex de Minaur in the final, and won his fourth ATP doubles title at the 2020 Sofia Open by a walkover from Jürgen Melzer and Édouard Roger-Vasselin.

[12] Two weeks later, he reached his second Masters-1000 final with compatriot Dan Evans at the Miami Open and entered the top 20 in the doubles rankings for the first time.

Seeded seventh, they reached their second Masters 1000 final at the 2022 Mutua Madrid Open after defeating John Isner and Hubert Hurkacz.

[16] In the final they defeated fifth seeds Robert Farah and Juan Sebastián Cabal to win their first Masters 1000 title in their career and as a pair.

[17] At the 2022 French Open he reached the quarterfinals with Koolhof for the second time at this Major, defeating unseeded pair of Americans Tommy Paul and Mackenzie McDonald.

[25] At the 2022 Rolex Paris Masters the pair Koolhof/Skupski reached the semifinals defeating ninth seeds Rohan Bopanna/Matwe Middelkoop climbing to World No.

1 duo Koolhof and Skupski continued their good form reaching yet another Masters final at the 2023 BNP Paribas Open where they lost to Rohan Bopanna and Matthew Ebden.

[31][32] Skupski and Desirae Krawczyk reached the mixed doubles final at the Australian Open in January losing to Hsieh Su-wei and Jan Zielinski 6-7 (5-7) 6-4 11-9.

[33] The pair also suffered similar disappointment at the French Open in June, when they lost out in the final 6-4 7-5 to Laura Siegemund and Edouard Roger-Vasselin.

[34] At the Queen's Club Championships, he combined with Michael Venus to win the doubles title, defeating Taylor Fritz and Karen Khachanov in the final.

[36] Skupski is considered Andy Murray's biggest rival in their Fantasy Premier League, "His knowledge isn't that high level, but he spends hours on the apps and websites.