De Silvestro raced in the Atlantic Championship in 2008 for Newman Wachs Racing, winning at the Grand Prix of Long Beach to become only the second woman to win in that series after Katherine Legge. She returned in 2009 for Team Stargate Worlds, winning four times and leading the points standings for much of the season before finishing third after retiring on the first lap of the finale at Mazda Raceway Laguna Seca.
De Silvestro made her IndyCar debut in 2010 with HVM Racing and qualified 22nd for the Indianapolis 500, finishing 14th and earning the Indianapolis 500 Rookie of the Year honour. Her season was marked by a fiery crash at Texas Motor Speedway that left her with a burned right hand. She recorded two top-ten finishes that year with a best result of eighth at Mid-Ohio.
The 2011 season saw her sustain second-degree burns on her right hand during Indianapolis 500 practice following a mechanical failure that sent her car into the catch fence. Despite returning to race, her season was interrupted by visa troubles that prevented her competing at Sonoma.
For 2012 her HVM Racing entry was saddled with the uncompetitive Lotus engine when every other team abandoned the powerplant; the underpowered car resulted in consistently poor results including being black-flagged at the Indianapolis 500 for failing to maintain minimum safe speed.
De Silvestro moved to KV Racing Technology alongside Tony Kanaan for 2013. At the Grand Prix of Houston she finished second in Race 1, her first podium finish in IndyCar and only the third podium finish by a woman in the series' history. She made additional IndyCar appearances with Andretti Autosport in 2015 and with Paretta Autosport at the 2021 Indianapolis 500.
In February 2014 Sauber announced de Silvestro as an affiliated driver on a training programme aimed at a race seat in 2015. She completed a test at Fiorano in a 2012 Sauber, covering 112 laps. However, Sauber suspended the arrangement in October 2014 citing contractual difficulties.
De Silvestro drove for Andretti's Formula E team at the 2015 London double-header finale, then joined the squad full-time for the 2015-16 season. She became the first woman to score points in Formula E with a ninth place at the 2016 Long Beach ePrix, finishing the championship eighteenth with four points.
De Silvestro entered the Supercars world as a co-driver for Prodrive Racing Australia alongside Renee Gracie in the 2015 Bathurst 1000, the pair finishing 21st after an early wall impact. The following year she paired with Gracie again, this time under the Nissan Motorsport banner, and managed to finish 14th in the Bathurst 1000's chaotic late stages.
On 5 September 2016, Nissan Motorsport announced de Silvestro as a full-time Supercars driver from 2017. Her debut season proved difficult, with incidents including being spun by James Courtney in Adelaide, a late-race crash at Bathurst 1000 while running in the top ten, and being fenced by rivals at the Newcastle season finale. She improved to 23rd overall in 2018, including her first top-ten finish in a fuel conservation race in Newcastle.
For 2019, amid interest from Triple Eight Race Engineering, de Silvestro remained at what had become Kelly Racing after losing Nissan factory support. She recorded a best result of 7th in New Zealand but otherwise struggled with the now-underpowered Nissan Altimas, announcing her departure before the Sandown round and finishing the season 19th. She made a cameo return to Supercars at the 2023 Bathurst 1000 as a wildcard entry for Dick Johnson Racing alongside rookie Kai Allen, finishing 20th.
In early 2022 de Silvestro announced she had begun bobsleigh training with the goal of competing for Italy at the 2026 Winter Olympics in Milan-Cortina. She placed fifth at the 2022 Swiss championships in her first competitive event. Through the 2025-26 Bobsleigh World Cup she qualified for both the monobob and two-person events at the 2026 Winter Olympics.
Simona de Silvestro's career stands as one of the most geographically and categorically diverse in modern motorsport. As one of very few women to have raced full-time in IndyCar, earned a Formula E points finish, and completed multiple Supercars seasons, she consistently competed at the top level across three continents. Her athletic second act in bobsleigh added an Olympic dimension that few professional racing drivers have ever matched.