[2] Considered one of the best servers ever to play on the ATP Tour, Isner achieved his career-high singles ranking in July 2018 by virtue of his first Masters 1000 crown at the 2018 Miami Open and a semifinal appearance at the 2018 Wimbledon Championships.

At the following week's tournament at the Legg Mason Tennis Classic in Washington, D.C., a late withdrawal freed up a wildcard spot, which was given to Isner at the last minute.

He proceeded to win his second-round match against Rik de Voest, before losing in the third round to top seed and eventual champion Roger Federer.

In April 2009 at the U.S. Men's Clay Court Championships in Houston, Texas, at River Oaks Country Club, Isner made it as far as the quarterfinals, where he was defeated by fellow American Wayne Odesnik.

Prior to the Davis Cup tie, Isner competed at the 2010 Abierto Mexicano Telcel Championships, an ATP World Tour 500 event on clay, where he was the fifth seed.

89 Xavier Malisse at the U.S. Men's Claycourt Championship, followed by a round of 32 showing at his first-ever Internazionali BNL d'Italia, where he defeated Horacio Zeballos, before losing to Thomaz Bellucci.

19 in the world entering Wimbledon, Isner was seeded 24th by the tournament committee due to his lack of experience on grass, but was moved up to 23rd following the withdrawal of Radek Štěpánek.

Isner next competed at the 2010 Legg Mason Tennis Classic, the ATP World Tour 500 series event in Washington, D.C., and site of his breakthrough performance in 2007.

After defeating Łukasz Kubot in the first round, he faced 2002 Wimbledon finalist and 2005 Tennis Masters Cup champion David Nalbandian, but was forced to retire up a break at 5–4 in the first set after injuring his right ankle.

Isner began the year by teaming with Bethanie Mattek-Sands to win the mixed doubles Hopman Cup final for the United States, defeating Belgium's Justine Henin and Ruben Bemelmans.

[40] Isner next played at the 2011 Australian Open He entered the tournament seeded 20th[41] and received a tough draw, including Radek Štěpánek, Marin Čilić, and Rafael Nadal.

[42] In the 2011 Wimbledon men's singles draw, Isner was paired against Mahut in the first round, a rematch of the world's longest match from the previous year's tournament.

Isner then accepted a last-minute wildcard to participate in the 2011 Hall of Fame Tennis Championships, replacing compatriot and defending champion Mardy Fish, who was chosen to play in the Davis Cup for the United States during that weekend.

Isner was the top seed and defeated Karol Beck, Arnaud Clément, Alex Bogomolov Jr., and Tobias Kamke without dropping a set, to reach his first career grass-court final.

He then reached the semifinals of the Legg Mason Tennis Classic, defeating Tobias Kamke, James Blake and Viktor Troicki before losing to Gaël Monfils.

3 Roger Federer in Switzerland in the first round of the Davis Cup, as well as beating Marco Chiudinelli in another singles rubber, to help propel the United States to victory over the Swiss.

During a busy summer, he reached another final in Cincinnati, beating Richard Gasquet and then three top-10 players in a row, first Milos Raonic, then Novak Djokovic, followed by a maiden triumph over Juan Martín del Potro in the semifinals.

Isner then reached the semifinals of the Delray Beach International Tennis Championships, losing to eventual champion Marin Čilić in straight sets.

[50] At the 2016 Australian Open, he reached the fourth round for the first time in six years, defeating Spaniards Marcel Granollers and Feliciano López before losing to David Ferrer in straights sets.

[52] In the first round of the 2016 Davis Cup, Isner defeated Bernard Tomic and Sam Groth to help upset Australia 3–1 and move the United States into the quarterfinals against Croatia.

At the Dell Technologies Hall of Fame Open in Newport, Isner defeated qualifier Matthew Ebden 6–3, 7–6 in the final to win his first singles title of the year.

Isner won the Atlanta BB&T Open on July 30, defeating fellow countryman Ryan Harrison 7–6, 7–6 in two evenly contested tiebreak sets.

In July 2021, Isner won his sixth ATP doubles title at the 2021 Los Cabos Open, partnering with Hans Hach Verdugo as wild-card entries.

[70] At the 2021 Atlanta Open, Isner defeated Brandon Nakashima to win a record sixth title in his ninth finals appearance at the event.

Isner partnered with Jack Sock in doubles at Indian Wells and they won the title, beating Santiago González and Édouard Roger-Vasselin in the final.

[72] Isner next partnered with Hubert Hurkacz for the 2022 Miami Masters and defeated reigning 2022 Australian Open champions Thanasi Kokkinakis and Nick Kyrgios in the semifinals and then the sixth-seeded Wesley Koolhof and Neal Skupski in the final.

In Newport, Isner reached what would be the last semifinal of his career, after beating Alex Bolt, Corentin Moutet, and top seed Tommy Paul.

The second-longest match in major tournament history was Isner's loss to South African Kevin Anderson in the first men's semifinal at the 2018 Wimbledon Championships.

[96] Isner had an extremely powerful and consistent serve, thanks in part to his 6-foot-10½-inch height which made him the third-tallest player in tour history, behind Ivo Karlović and Reilly Opelka.

Isner then hired Mike Sell, who helped him to significant success, such as defeating Roger Federer, David Nalbandian and Novak Djokovic.