For her work on stage, Atwell has received Laurence Olivier Award nominations for her leading performances in The Pride (2013) and Rosmersholm (2020).

[1] Atwell made her professional stage debut in Prometheus Bound (2005) at the Sound Theatre in London, portraying Io, a maiden exiled by Zeus.

[10] Her role received positive reviews with the British Theatre Guide praising her performance, writing that she "makes us respond to the anguish without for a moment inviting a chuckle at her bandaged hands".

[13] Atwell appeared in two productions from 2007 to 2008 at the Royal National Theatre, both directed by Nicholas Hytner: Man of Mode and Major Barbara.

[18] In 2009, Atwell made her West End debut as Catherine, the adopted niece in a troubled household, in Lindsay Posner's A View From the Bridge.

[19] Variety praised her for having an "ideal freshness" and girlishness while still able to shift into uncontrolled rage; her performance was later nominated for an Olivier Award.

[21][22] In 2010 Atwell appeared in Channel 4's adaptation of William Boyd's Any Human Heart, and later that year, Ken Follett's miniseries Pillars of the Earth for which she received a Golden Globe Award nomination.

[23][24] In April 2010, Atwell was cast as the love interest in a then-forthcoming film about Captain America as part of the Marvel Cinematic Universe.

[31][32] In February of that year, she also starred in "Be Right Back", an episode in Charlie Brooker's critically acclaimed science fiction television series Black Mirror.

[34][35] That same year, Atwell also worked with Alexi Kaye Campbell and Jamie Lloyd again in a revival of The Pride at Trafalgar Studios.

[46][47] Atwell starred as Margaret Schlegel in BBC One's 2017–2018 miniseries, Howards End, based on the classic E.M. Forster novel and adapted by playwright Kenneth Lonergan.

In 2019, Atwell starred opposite Tamara Lawrance in a three-part BBC adaptation of Andrea Levy's novel The Long Song, about a slave on a sugar plantation in 19th-century Jamaica.

[57] In 2021, early reviews for Peter Rabbit 2: The Runaway revealed Atwell as part of the film's voice cast as Mittens the cat.

[67] In a 2015 interview, Atwell discussed how her role as Peggy Carter influenced a then-recent tweet she made to her Twitter followers about having her image digitally altered on the cover of a German magazine.