De Silvestro raced for Newman Wachs Racing's Nuclear Clean Air Energy-Entergy team in the Atlantic Championship in 2008. She won the Atlantic race at the 2008 Grand Prix of Long Beach, becoming the second woman to win in that series. She also raced for Team Stargate Worlds in 2009, winning four times during the season and leading in points for most of the season. De Silvestro ultimately finished third in the standings after retiring on the first lap during the season finale at Mazda Raceway Laguna Seca.
De Silvestro competed full-time in the IndyCar Series for HVM Racing for the 2010 season. She qualified in the 22nd position for the 2010 Indianapolis 500 and finished the race in 14th position, 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 and recorded two top-ten finishes, with a best finish of eighth at Mid-Ohio.
In 2011, de Silvestro received second-degree burns on her right hand during practice for the 2011 Indianapolis 500. The crash, which sent her car into the catch fence, was caused by a mechanical failure in the left rear of her No. 78 Dallara-Honda. She qualified 24th for the race using her backup car. 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 to be significantly underpowered compared to the Chevrolet and Honda engines used by the rest of the field. The underpowered engine made it impossible for de Silvestro to be competitive, resulting in consistently poor qualifying and race results. On 30 October 2012, de Silvestro signed on with KV Racing Technology for the 2013 IndyCar Series season, driving the No. 78 Dallara-Chevrolet. On 5 October 2013 at the Grand Prix of Houston, de Silvestro finished second in the first race for her first podium finish.
In February 2014, Formula One team Sauber announced that de Silvestro would join the team as an "affiliated driver." She began testing with the team at the end of April 2014 at Fiorano Circuit. 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. 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. Between 2019 and 2023, de Silvestro served as Porsche's reserve driver.
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. 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. De Silvestro improved to 23rd in the overall standings in 2018, claiming her first top-ten finish in a fuel conservation race in Newcastle. She finished the 2019 season 19th in the standings.
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 the winter sport of 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.
De Silvestro is of Italian descent through her father and holds dual Swiss and Italian citizenship.
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