In 2008, de Silvestro raced for Newman Wachs Racing's Nuclear Clean Air Energy-Entergy team in the Atlantic Championship. She won the Atlantic race at the 2008 Grand Prix of Long Beach, becoming the second woman to win in that series after Katherine Legge. De Silvestro raced for Team Stargate Worlds in 2009, winning four times and leading in points for most of the season, ultimately finishing third. She participated in an IndyCar Series test over 8–9 December 2009 at Sebring International Raceway, a joint effort between HVM Racing and Team Stargate Worlds.
De Silvestro competed full-time in the IndyCar Series for HVM Racing for the 2010 season. She qualified 22nd for the 2010 Indianapolis 500 and finished 14th, earning Indianapolis 500 Rookie of the Year honors. She suffered a burned right hand after a fiery crash at the Firestone 550 at Texas Motor Speedway on 5 June 2010. For the season, de Silvestro started seventeen races, finished ten, and recorded two top-ten finishes, with a best finish of eighth at Mid-Ohio. She finished nineteenth overall in the series standings and was runner-up to Alex Lloyd for rookie of the year honors.
The 2011 season began with fourth- and ninth-place finishes at St. Petersburg and Barber. At the São Paulo Indy 300, an accident with Hélio Castroneves put her nine laps down, though she recorded the fastest lap. De Silvestro received second-degree burns on her right hand and superficial burns on her left hand in a crash during practice for the 2011 Indianapolis 500 on 19 May, caused by a mechanical failure in her No. 78 Dallara-Honda. She qualified 24th for the race. After a crash at the Milwaukee Mile during qualifying, de Silvestro withdrew from the race due to dizziness and impaired vision. She was not cleared to compete at the next race in Iowa due to continuing dizziness. De Silvestro missed round 13 of the season at Sonoma after being refused entry to the United States. She finished twentieth overall in the 2011 series standings.
De Silvestro returned to HVM Racing for the 2012 IndyCar Series season, piloting the No. 78 Nuclear Clean Air Energy sponsored Dallara-Lotus. The Lotus engine proved significantly underpowered compared to Chevrolet and Honda engines. De Silvestro was saddled with the inferior Lotus for the entire season, leading to consistently poor results and black flags for failing to maintain minimum safe speed, including at the 2012 Indianapolis 500. She qualified for all fifteen races, started fourteen, and finished six, with a best finish of 14th at Detroit and Iowa. She finished 24th overall in the series standings.
On 30 October 2012, de Silvestro signed with KV Racing Technology for the 2013 IndyCar Series season, driving the No. 78 Dallara-Chevrolet with sponsorship from Nuclear Clean Air Energy. She joined Tony Kanaan to make KV Racing Technology a two-car team. On 5 October 2013 at the Grand Prix of Houston, de Silvestro finished second in the first race for her first podium finish, joining Danica Patrick and Sarah Fisher as the only women in IndyCar history to record a podium finish.
On 2 April 2015, de Silvestro announced she would drive the Andretti Autosport No. 29 Honda in the 2015 IndyCar Series season in an attempt to make the Indianapolis 500. She finished fourth in the second race of the season, the Indy Grand Prix of Louisiana. On 19 January 2021, Paretta Autosport announced their IndyCar debut at the 2021 Indianapolis 500 with de Silvestro as the driver in the No. 16 Rocket Pro Chevrolet.
In February 2014, Formula One team Sauber announced that de Silvestro would join the team as an "affiliated driver" and undergo a year-long training programme with the ultimate objective of racing in 2015. De Silvestro began testing with the team at the end of April 2014 at Fiorano Circuit. She had her first drive in the 2012 Sauber on 26 April, completing 112 laps. However, in October 2014, Sauber team principal Monisha Kaltenborn stated that the team had suspended de Silvestro's driving chances due to contractual troubles.
On 15 June 2015, it was announced de Silvestro would drive for Andretti's Formula E team at the championship's double-header finale in London. She was confirmed with the team full-time for the 2015-16 season opposite Formula Renault 3.5 champion Robin Frijns. In 2016, de Silvestro became the first female driver to score points in Formula E with a ninth place in the 2016 Long Beach ePrix. She finished the championship in eighteenth place with four points.
De Silvestro returned to the driving seat for Venturi Racing at the December 2018 Ad Diriyah test, placing tenth overall and fastest of all female drivers. Between 2019 and 2023, de Silvestro served as Porsche's reserve driver. In 2024, she participated in the all-female pre-season test held at Circuito del Jarama, joining new team Kiro Race Co..
On 19 August 2015, it was announced that de Silvestro would partner Renee Gracie at Prodrive Racing Australia in the Bathurst 1000 for V8 Supercars. The car underwent extensive repairs after an impact with the wall and finished 21st. On 5 September 2016, it was announced that de Silvestro had signed a three-year contract as a full-time driver for Nissan Motorsport in the Australian Supercars Championship, beginning from the 2017 season. This followed another appearance at Bathurst alongside Gracie, this time with the Nissan squad, where they finished 14th.
De Silvestro suffered a tumultuous debut season, starting on the back foot when she was spun by James Courtney in Adelaide. Strong performances at the season finale in Newcastle went unrewarded when she was fenced by Tim Slade in the first race and spun by championship contender Scott McLaughlin in the second. De Silvestro improved to 23rd in the overall standings in 2018, claiming her first top-ten finish in a fuel conservation race in Newcastle. Following interest from Triple Eight Race Engineering, de Silvestro remained with Kelly Racing for 2019. She picked up a best result of 7th in New Zealand following a safety car bungle. The Swiss confirmed her exit from the championship prior to the penultimate round at Sandown, finishing the season 19th in the standings. De Silvestro made a cameo appearance in the 2023 Bathurst 1000 as a wildcard entry for Dick Johnson Racing; sharing a Ford Mustang with rookie Kai Allen, the pair finished 20th.
In 2020, de Silvestro returned to Europe as a factory Porsche GT driver, contesting the 2020 ADAC GT Masters for Timo Bernhard's Team75 with Klaus Bachler. She finished 23rd in the championship with 41 points. The duo switched to Herberth Motorsport for the 2021 ADAC GT Masters.
In early 2022, de Silvestro announced that she had started training in bobsleigh, with a goal to compete for Italy at the 2026 Winter Olympics in monobob. Her first competitive event was the 2022 Swiss championships where she placed fifth. De Silvestro qualified for both the monobob and two-person disciplines through her results in the 2025–26 Bobsleigh World Cup, finishing 23rd overall in both.
De Silvestro is of Italian descent through her father and holds dual Swiss and Italian citizenship.
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