She also appeared as Jem in the Black Mirror episode "White Bear" (2013), as Miss Havisham in Dickensian (2015–2016), as Russian princess Hélène Kuragina in War & Peace (2016), and as Riley "Blue" Gunnarsdóttir in Sense8 (2015–2018).

[10] In 2013, she made her professional theatre debut in The Living Room,[11] before playing a minor role in Danny Boyle's psychological thriller film Trance and giving a highly praised performance in the Black Mirror episode "White Bear".

[12][13][14] In 2014, after working on Lilly and Lana Wachowski's space opera film Jupiter Ascending (2015), she joined the main cast of their Netflix science fiction series Sense8 (2015–2018).

The Daily Express said: "Rising star Tuppence Middleton takes on the role of the delightfully evil Hélène Kuragina, who is one half of the incestuous duo.

This film was soon followed by the psychological horror Possessor (2020), the Netflix-distributed historical miniseries The Defeated (2020), also known as Shadowplay, and David Fincher's biographical drama Mank (2020), in which she portrayed the wife of Herman J. Mankiewicz, the co-writer of Citizen Kane (1941).

[22][23] In 2021, Middleton also narrated an immersive step inside a story audiovisual tour for Hyde Park in London based around The Great Exhibition and written by Elizabeth Macneal for the BARDEUM mobile app.

[27] She currently is starring in the National Theatre as Elizabeth Taylor in the Sam Mendes directed Jack Thorne play The Motive and the Cue opposite Johnny Flynn as Richard Burton and Mark Gatiss as Sir John Gielgud.

[30] Middleton revealed that she "struggles with self-imposed routines that sometimes stop her leaving the house, as well as obsessive mental counting and compulsive checking behaviours".