Comer's professional career began in 2008 with a guest role on an episode of The Royal Today, a spin-off series of the medical drama series The Royal. She then made appearances in series such as Waterloo Road, Holby City, Doctors, Silent Witness, Casualty, Law & Order: UK, Vera, and Inspector George Gently. She was cast in leading roles in the five-episode drama series Justice, the supernatural miniseries Remember Me, and as Chloe Gemell in the E4 comedy-drama series My Mad Fat Diary. Comer appeared in the 2015 adaptation of Lady Chatterley's Lover, a television film broadcast on BBC One. That same year, she appeared as Kate Parks in the BBC One drama series Doctor Foster and was cast in her first starring role as Ivy Moxam in the BBC Three miniseries Thirteen, which premiered in February 2016 and earned her a nomination for the British Academy Television Award for Best Actress. In December 2016, she appeared in the BBC miniseries Rillington Place. In 2016, Comer was listed as one of Screen International's "Stars of Tomorrow" in association with the BFI London Film Festival. In 2017, she starred as a young Elizabeth of York in The White Princess on Starz, a sequel to the BBC miniseries The White Queen. In 2017, she also made her feature film debut, as Christine in the Morrissey biopic England is Mine.