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. In 2009, she raced for Team Stargate Worlds and won four times, leading in points for most of the season before finishing third.
She competed full-time in the IndyCar Series for HVM Racing in 2010. De Silvestro 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 in June 2010. For the season, she 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 due to a mechanical failure in her No. 78 Dallara-Honda. She qualified 24th for the race using her backup car. She missed round 13 of the season at Sonoma after being refused entry to the United States. De Silvestro returned to HVM Racing for the 2012 IndyCar Series season, piloting the No. 78 Dallara-Lotus. The Lotus engine proved significantly underpowered, leading to consistently poor results.
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, she 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. In 2015, de Silvestro drove the Andretti Autosport No. 29 Honda in an attempt to make the Indianapolis 500. She finished fourth in the second race of the season, the Indy Grand Prix of Louisiana. In 2021, Paretta Autosport announced de Silvestro would drive the No. 16 Rocket Pro Chevrolet at the 2021 Indianapolis 500.
In February 2014, Sauber announced 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 suspended her driving chances due to contractual troubles.
De Silvestro drove for Andretti's Formula E team at the championship's finale in London in June 2015. 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. 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. The pair finished 21st. In 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 a cameo appearance in the 2023 Bathurst 1000 as a wildcard entry for Dick Johnson Racing.
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.
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. She qualified for both the monobob and two-person disciplines through her results in the 2025–26 Bobsleigh World Cup.
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