Pagenaud grew up in Montmorillon, where his family operated a supermarket. He began karting around age ten, and his first significant competitive result came in 2000 when he won the Volant Elf driver development competition. He moved into Formula Renault Campus in 2001 as a runner-up, then competed in French Formula Renault in 2002 and 2003, with additional seasons in Formula Renault Eurocup in 2002 and 2004. A move to the Formula Renault 3.5 Series in 2005 produced a sixteenth-place finish.
In 2006 Pagenaud traveled to the United States and won the Champ Car Atlantic championship with Team Australia in his rookie season, edging Graham Rahal by a narrow margin. The title came with a US$2 million prize toward a Champ Car seat. He duly joined Team Australia in Champ Car for 2007, finishing eighth in the standings in a consistent debut that included three consecutive fourth-place finishes in the Canadian rounds.
After Champ Car folded, Pagenaud moved to the American Le Mans Series for 2008, co-driving the De Ferran Motorsports Acura ARX-01b LMP2 car with former CART champion Gil de Ferran. The partnership improved dramatically in 2009, finishing second overall in the LMP1 class with three race wins and three pole positions across ten races, only 17 points behind champions Highcroft Racing.
For 2010 Pagenaud joined the Patron Highcroft Racing team, co-driving with David Brabham in the ARX-01c. Through four rounds the pair led the LMP1 class with three wins and 91 points, and Pagenaud took the American Le Mans Series LMP1 class championship that year — his first major professional title.
Pagenaud also raced at the 24 Hours of Le Mans in 2009 for Pescarolo Sport in the Peugeot 908, and in 2010 as part of the Peugeot factory team alongside Pedro Lamy and Sebastien Bourdais in the No. 3 car, which retired early after 38 laps due to a suspension mount failure.
Pagenaud moved to the IndyCar Series, and in 2014 won the inaugural Grand Prix of Indianapolis on 10 May. He joined Team Penske for the 2015 season. At the 2015 Indianapolis 500 he led with fewer than thirty laps remaining but was overtaken by the field and finished tenth while teammate Juan Pablo Montoya won.
In 2016 Pagenaud delivered his best IndyCar season, opening with five consecutive podiums including three consecutive race wins. He and teammate Will Power became the primary championship contenders; Pagenaud ultimately won his first IndyCar Series championship with five race victories and eight podiums across the season, giving Team Penske a championship title in its fiftieth year of racing.
After a winless 2018, Pagenaud won the 2019 Grand Prix of Indianapolis and then the 2019 Indianapolis 500 from pole position. The victory was the first by a French-born driver at Indianapolis since Gaston Chevrolet's triumph in 1920, a gap of 99 years. He also won the 2019 Honda Indy Toronto from pole that season, finishing the year second in the championship behind teammate Josef Newgarden.
In 2020 Pagenaud won the Iowa IndyCar 250 at Iowa Speedway Race 1, leading from lap 178 after starting 23rd following a fuel pump failure in qualifying — his final IndyCar victory. After a difficult 2021 season in which his contract with Penske expired, Pagenaud joined Meyer Shank Racing for 2022 alongside Helio Castroneves, though the team lost competitiveness as the season progressed. He finished fifteenth in the standings.
During the 2023 season, at the Honda Indy 200 at Mid-Ohio, Pagenaud suffered a severe crash in which his car flipped multiple times. He credited IndyCar's aeroscreen with saving his life. Injuries forced him to sit out the remainder of the season, and he was subsequently dropped from Meyer Shank Racing.
Pagenaud won both the 2022 and 2023 24 Hours of Daytona with Meyer Shank Racing. He also returned to the 24 Hours of Le Mans in 2023 for Cool Racing in the LMP2 class, his first start at the race since 2011.
In 2025 Pagenaud was announced as a simulator driver for the Cadillac Formula One Team as that organization prepared for its Formula One entry.
During the 2020 iRacing virtual Indianapolis 500, Pagenaud was accused of deliberately crashing into lead driver Lando Norris, which generated significant criticism around sportsmanship in virtual racing.
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