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 after Katherine Legge. In 2009, she raced for Team Stargate Worlds, winning four times and leading in points for most of the season before finishing third. De Silvestro participated in an IndyCar Series test in 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 in 2010. 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 crash at the Firestone 550 at Texas Motor Speedway. For the season, she recorded two top-ten finishes, with a best of eighth at Mid-Ohio, and finished 19th overall in the series standings.
The 2011 season began with fourth- and ninth-place finishes at St. Petersburg and Barber. At the São Paulo Indy 300, an accident put her nine laps down, though she recorded the fastest lap. De Silvestro received second-degree burns in a crash during practice for the 2011 Indianapolis 500. She qualified 24th for the race using her backup car. After a crash at the Milwaukee Mile, she withdrew from the race due to dizziness and impaired vision, and was not cleared to compete at Iowa. De Silvestro missed round 13 of the season at Sonoma after being refused entry to the United States. She finished 20th overall in the 2011 series standings.
De Silvestro returned to HVM Racing for the 2012 IndyCar Series season, piloting a Dallara-Lotus. The Lotus engine proved significantly underpowered compared to Chevrolet and Honda engines. She was saddled with the inferior Lotus for the entire season, leading to poor results and black flags for failing to maintain minimum safe speed, including at the 2012 Indianapolis 500. Her best finish was 14th at Detroit and Iowa, and 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 a Dallara-Chevrolet. On 5 October 2013 at the Grand Prix of Houston, she finished second in the first race, achieving her first podium finish. This made her one of only three women in IndyCar history, alongside Danica Patrick and Sarah Fisher, to record a podium finish.
On 2 April 2015, de Silvestro announced she would drive for Andretti Autosport in the 2015 IndyCar Series season to attempt 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 de Silvestro would drive for them at the 2021 Indianapolis 500.
In February 2014, Sauber F1 Team announced de Silvestro would join as an "affiliated driver" with the goal of racing in 2015. She began testing with the team at Fiorano Circuit in April 2014, completing 112 laps in a 2012 Sauber. However, in October 2014, Sauber suspended her driving chances due to contractual troubles.
On 15 June 2015, de Silvestro was announced to drive for Andretti's Formula E team at the championship's finale in London. She was confirmed 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 18th place with four points.
De Silvestro returned for Venturi Racing at the December 2018 Ad Diriyah test, placing tenth overall and fastest among female drivers. Between 2019 and 2023, she served as Porsche's reserve driver. In 2024, she participated in the all-female pre-season test at Circuito del Jarama, joining new team Kiro Race Co.
On 19 August 2015, de Silvestro was announced to partner Renee Gracie at Prodrive Racing Australia in the Bathurst 1000 for V8 Supercars. They finished 21st. On 5 September 2016, de Silvestro signed a three-year contract as a full-time driver for Nissan Motorsport in the Australian Supercars Championship, starting from the 2017 season. She made another appearance at Bathurst alongside Gracie with the Nissan squad, finishing 14th.
De Silvestro had a tumultuous debut season in 2017, experiencing incidents in Adelaide, Tasmania, and Phillip Island. At the Bathurst 1000, she crashed with less than ten laps remaining. Strong performances at the Newcastle season finale went unrewarded due to incidents. She finished as the lowest-classified driver in the standings to complete every event.
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, she remained with Kelly Racing for 2019. She achieved a best result of 7th in New Zealand but otherwise struggled. De Silvestro confirmed her exit from the championship before 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 Kai Allen and finishing 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 she had started training in bobsleigh, aiming 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 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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