Killing Eve and breakthrough (2018–2021)
In April 2018, Comer began starring in the BBC America spy thriller series Killing Eve as Villanelle / Oksana Astankova, a sociopathic Russian assassin who develops a mutual obsession with Eve Polastri (Sandra Oh), the MI6 agent pursuing her. Comer garnered praise for her performance; Jia Tolentino of The New Yorker stated that, in the context of the series's "constant reversals in tone and rhythm", the "ambiguity—and impossibility—of Villanelle's character has worked (through the first season) thanks to Comer's mercurial, unassailable charisma".
After the first season of Killing Eve aired, Comer revealed how much she'd learned from embodying her character, stating: "I had this impression that, to do good acting, everything is minimal, really whispered, less is more. What I learned playing Villanelle is that there is acting that can be so full of life and bold that it is ridiculous at times. There was something very freeing about playing her." For the role, Comer was thrice nominated for the British Academy Television Award for Best Actress and Primetime Emmy Award for Outstanding Lead Actress in a Drama Series, winning both in 2019. Given her character's ability to adopt numerous accents as part of her disguises, fans are often astonished to hear Comer's native Scouse accent.
In June 2018, Comer played Linda, a 1960s Liverpool secretary exploring her sexuality, in the BBC Four series Snatches: Moments from Women's Lives, inspired by events that took place in the century since women first won the vote. In August 2018, Comer was ranked No. 94 on Radio Times's TV 100. In November 2018, The Hollywood Reporter included her in their list of the "Next Gen Talent 2018: Hollywood's Rising Young Stars".
In April 2019, Comer revealed she had been forced to drop out of Kenneth Branagh's 2022 adaptation of Agatha Christie's Death on the Nile due to scheduling conflicts. Also in 2019, Comer made a cameo appearance in the film Star Wars: The Rise of Skywalker, appearing as Rey's mother (Miramir) in a flashback. In June 2020, Comer played the lead role of Lesley in a BBC iPlayer reboot of the Talking Heads episode "Her Big Chance" (filmed in lockdown due to the COVID-19 pandemic). Comer next appeared in the action comedy film Free Guy, alongside Ryan Reynolds, in which she played two roles: Millie, a games developer, and Molotov Girl, Millie's in-game avatar. Released on 13 August 2021, a cover version of Mariah Carey song "Fantasy" (1995) sung by Comer was used in the film. For the role, she was nominated for the Saturn Award for Best Supporting Actress.
Later in 2021, Comer teamed with writer Jack Thorne and actor Stephen Graham to star in the Channel 4 drama Help, as a young care home worker struggling during the early days of the COVID-19 pandemic in the United Kingdom; she also served as an executive producer. The role earned her a fifth British Academy Television Award for Best Actress nomination, which she ultimately won the following year. Also in 2021, Comer portrayed Marguerite de Carrouges in Ridley Scott's The Last Duel, alongside Ben Affleck, Matt Damon and Adam Driver.
