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, making her the second woman to win in that series. In 2009, she raced for Team Stargate Worlds and won four times, leading in points for most of the season before finishing third overall. 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, de Silvestro recorded two top-ten finishes, with a best finish of eighth at Mid-Ohio, and finished nineteenth overall in the series standings.
In 2011, de Silvestro received second-degree burns on her right hand during practice for the 2011 Indianapolis 500. The crash was caused by a mechanical failure in her No. 78 Dallara-Honda. She later 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. This resulted in consistently poor qualifying and race results, and the car was black flagged for failing to maintain the minimum safe speed, including at the 2012 Indianapolis 500. 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. At the Grand Prix of Houston on 5 October 2013, de Silvestro finished second, achieving her first podium finish. In 2015, she drove the Andretti Autosport No. 29 Honda in the 2015 IndyCar Series season and finished fourth at the Indy Grand Prix of Louisiana. In 2021, Paretta Autosport announced de Silvestro would drive for them at the 2021 Indianapolis 500.
In February 2014, Sauber announced that de Silvestro would join the team as an "affiliated driver" with the objective 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 team principal Monisha Kaltenborn stated that the team had suspended de Silvestro's driving chances due to contractual troubles.
On 15 June 2015, de Silvestro was announced as a driver 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 eighteenth place with four points. De Silvestro returned to drive for Venturi Racing at the December 2018 Ad Diriyah test, placing tenth overall and fastest among 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 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 pair finished 21st after extensive repairs. 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 suffered a tumultuous debut season in 2017, finishing as the lowest-classified driver in the standings to complete every event. She improved to 23rd in the overall standings in 2018, claiming her first top-ten finish in Newcastle. De Silvestro remained with Kelly Racing for 2019, picking up a best result of 7th in New Zealand. She 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, 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 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.
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