De Silvestro entered the Atlantic Championship in 2008, racing for Newman Wachs Racing. She won the Atlantic race at the Grand Prix of Long Beach that year, becoming the second woman to win in the series after Katherine Legge and giving Newman Wachs Racing its first victory. In 2009 she won four times during the season and led the championship standings for much of the year before finishing third after retiring on the first lap at the season finale at Mazda Raceway Laguna Seca. She completed an IndyCar Series test at Sebring in December 2009 in a joint effort between HVM Racing and Team Stargate Worlds.
De Silvestro made her full IndyCar debut in 2010 with HVM Racing. She qualified for the 2010 Indianapolis 500 in 22nd and finished 14th, earning Indianapolis 500 Rookie of the Year honours. A fiery crash at Texas Motor Speedway during the Firestone 550 resulted in a burned right hand; her team publicly criticised IndyCar safety officials for their response. She started seventeen races that season, finishing ten, with a best result of eighth at Mid-Ohio.
In 2011 she sustained second-degree burns to her right hand and superficial burns to her left in a crash during practice for the Indianapolis 500, caused by a mechanical failure in the left rear of her car. She qualified 24th using a backup car with a four-lap average of 224.392 mph. Later that season she was refused entry to the United States, missing a round at Sonoma.
She returned to HVM Racing in 2012, spending the entire season as the only remaining entrant persisting with the Lotus engine after all other teams had switched to Chevrolet or Honda. The significantly underpowered Lotus left her unable to be competitive, and the car was black-flagged on several occasions for failing to maintain minimum safe speed, including at the Indianapolis 500. She qualified for all fifteen races, started fourteen, and finished six, with a best result of 14th.
De Silvestro joined KV Racing Technology for 2013. At the Grand Prix of Houston she finished second in the opening race, recording her first IndyCar podium and joining Danica Patrick and Sarah Fisher as the only women in IndyCar history to achieve a podium finish. In 2015 she drove for Andretti Autosport, finishing fourth in the Indy Grand Prix of Louisiana in only her second race of the season. She returned for the 2021 Indianapolis 500 with Paretta Autosport, driving the No. 16 Rocket Pro Chevrolet.
In February 2014, Sauber announced de Silvestro as an affiliated driver for a year-long training programme aimed at a race seat in 2015. She completed 112 laps in a test at Fiorano Circuit in April 2014 driving the 2012 Sauber. In October 2014, team principal Monisha Kaltenborn announced that the arrangement had been suspended due to contractual difficulties.
De Silvestro joined Andretti's Formula E team for the double-header season finale in London in June 2015 and was confirmed full-time for the 2015–16 season. In 2016 she became the first female driver to score points in Formula E with a ninth-place finish at the Long Beach ePrix, finishing the championship 18th overall with four points. She participated in the Venturi Racing test at Ad Diriyah in December 2018, placing tenth overall and fastest of all female drivers present. She served as Porsche's reserve driver between 2019 and 2023, and in 2024 participated in an all-female pre-season Formula E test at Circuito del Jarama with new team Kiro Race Co.
De Silvestro made her Australian Supercars debut at the 2015 Bathurst 1000, partnering Renee Gracie for Prodrive Racing Australia. After Gracie suffered a wall impact the car was extensively repaired and classified 21st. She partnered Gracie again at Bathurst in 2016 under the Nissan banner, finishing 14th.
She signed a three-year full-time contract with Nissan Motorsport for the 2017 Supercars season. Her debut was difficult, compounded by a spin caused by James Courtney at Adelaide, and she finished as the lowest-classified driver to complete every event. In 2018 she improved to 23rd overall, claiming her first Supercars top-ten in a fuel conservation race at Newcastle. She remained with the rebranded Kelly Racing for 2019, posting a best result of seventh in New Zealand before confirming her exit prior to the penultimate round, finishing 19th in the standings. De Silvestro made a wildcard appearance at the 2023 Bathurst 1000 for Dick Johnson Racing, sharing a Ford Mustang with Kai Allen and finishing 20th.
De Silvestro returned to Europe in 2020 as a factory Porsche GT driver, contesting the ADAC GT Masters for Team75 Bernhard alongside Klaus Bachler and finishing 23rd in the championship. She and Bachler switched to Herberth Motorsport for the 2021 ADAC GT Masters.
In early 2022, de Silvestro announced she had begun training in bobsleigh with a goal of representing Italy at the 2026 Winter Olympics in the monobob discipline. Her first competitive bobsleigh event was the 2022 Swiss championships, where she placed fifth. She subsequently qualified for both the monobob and two-person events through her results in the 2025–26 season.