De Silvestro raced in the Atlantic Championship in 2008 for Newman Wachs Racing, winning at the Grand Prix of Long Beach — only the second woman in series history to win a race, after Katherine Legge. In 2009 she won four races and led the points standings for much of the season but finished third after retiring on the first lap of the season finale at Mazda Raceway Laguna Seca.
De Silvestro made her IndyCar debut in 2010 with HVM Racing, qualifying 22nd for the Indianapolis 500 and finishing 14th to earn Indianapolis 500 Rookie of the Year honours. She suffered burns to her right hand in a fiery crash at Texas Motor Speedway that season. The 2011 season brought further misfortune: she received second-degree burns on her right hand and superficial burns on her left in a practice crash at the Indianapolis 500, yet qualified and competed.
The 2012 season was hampered by being saddled with the underpowered Lotus engine, which the rest of the field abandoned by late May; de Silvestro ran it for the entire year, making competitive results essentially impossible.
She moved to KV Racing Technology for 2013 and achieved a breakthrough: at the Grand Prix of Houston she finished second in the first race, becoming only the third woman in IndyCar history to achieve a podium finish, after Danica Patrick and Sarah Fisher. She raced for Andretti Autosport in 2015 and appeared at the 2021 Indianapolis 500 with Paretta Autosport.
In February 2014, Sauber announced de Silvestro as an affiliated driver with a year-long training programme aimed at an eventual race seat. She completed 112 laps in her first test at Fiorano in April 2014. However, the programme was suspended by October 2014 due to contractual complications, and the race seat never materialised.
De Silvestro drove for Andretti's Formula E team at the 2015 London finale and continued with the team 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. She later served as Porsche's reserve driver between 2019 and 2023, and participated in the all-female pre-season Formula E test at Circuito del Jarama in 2024.
De Silvestro made her debut at the Bathurst 1000 in 2015 alongside Renee Gracie for Prodrive Racing Australia, finishing 21st. From 2017 she competed full-time for Nissan Motorsport across three seasons, becoming a fixture in the Australian Supercars Championship — one of the most physically and technically demanding touring car series in the world. Her best result was a seventh-place finish in New Zealand. She departed Kelly Racing (formerly Nissan Motorsport) after the 2019 season. She made a cameo at the 2023 Bathurst 1000 for Dick Johnson Racing, sharing a Ford Mustang with Kai Allen and finishing 20th.
Returning to Europe in 2020 as a Porsche factory GT driver, de Silvestro competed in the ADAC GT Masters for Team75 alongside Klaus Bachler, and continued with the championship into 2021 with Herberth Motorsport.
In early 2022, de Silvestro announced she had begun training in bobsleigh with the objective of representing Italy at the 2026 Winter Olympics in Milan-Cortina. She placed fifth at the 2022 Swiss championships and progressed through the international circuit, qualifying for both the monobob and two-person events at the 2026 Olympics via her results in the 2025–26 Bobsleigh World Cup. She finished 23rd overall in both World Cup disciplines.
De Silvestro is of Italian descent through her father and holds dual Swiss and Italian citizenship. Her career has spanned five decades of competition across at least seven distinct racing and sliding categories, making her one of the most versatile athletes in contemporary motorsport.