Balfe gained early recognition with roles in The Beauty Inside (2012) and H+: The Digital Series (2012–2013), along with appearances in films like Super 8 (2011), Now You See Me (2013), and Escape Plan (2013).

Her breakthrough came with her portrayal of Claire Fraser in the Starz historical drama Outlander (2014–present), a role that has earned four Golden Globe Award nominations.

[4] Balfe's modelling career highlights include opening and closing fashion shows for Chanel, Givenchy, Dolce & Gabbana, Moschino, Alberta Ferretti and Louis Vuitton.

[14] In 2013 she starred in the music videos for "First Fires" by British musician Bonobo[15] and for "Chloroform" by French band Phoenix, the latter directed by Sofia Coppola.

[18] Both the series and her performance have received critical acclaim,[19] with Richard Lawson of Vanity Fair saying "it helps immensely that Balfe is such an appealing actress, [she] makes Claire a spirited, principled, genuinely heroic heroine".

[20] Tim Goodman of The Hollywood Reporter wrote that Balfe is "reason enough to watch; she's a confident actress who brings various shades to her character.

[23] In December 2014, Entertainment Weekly named Balfe one of its 12 Breakout Stars of 2014;[24] that month she was also voted "Woman Of The Year" at BBC America's Anglophenia Fan Favorites tournament.

[31] Balfe co-starred in the film Money Monster (2016), directed by Jodie Foster and starring George Clooney and Julia Roberts.

She played the head of PR of a company whose stock bottoms out, causing a man to lose all of his savings and subsequently take hostages on a live TV show.

[32] Eric Hills of The Movie Waffler wrote "But it's relative newcomer Balfe who leaves the greatest impression; she's magnetic, stealing scenes even when her character is only glimpsed reacting to the situation on a background monitor.

[42] She previously lived in Los Angeles, where she started acting professionally, and in New York City, Paris, London, Milan, Hamburg, and Tokyo while working as a model.

[46] On 10 August 2019, Balfe married her long-time boyfriend, former band manager and businessman Anthony "Tony" McGill at St. Mary's Church in Bruton, Somerset.

[53] She has also hosted several campaigns selling shirts featuring her Outlander character Claire Fraser with proceeds benefiting World Child Cancer.

[54] In June 2023, Balfe appeared on BBC Radio 4 Appeal to share the story of one of the children World Child Cancer has supported.