He portrayed George Wickham in Pride & Prejudice (2005), Lieutenant Kurt Kotler in The Boy in the Striped Pyjamas (2008), Albert, Prince Consort in The Young Victoria (2009), psychologist Oliver Baumer in Starred Up (2013), CIA operative Peter Quinn in the political thriller series Homeland (2012–2017), Vasily Stalin in The Death of Stalin (2017), Theo van Gogh in At Eternity's Gate (2018), and Ernest Donovan in the series Strange Angel (2018–2019).

In the early 2020s, Friend began collaborating with director Wes Anderson, starting with a cameo in The French Dispatch (2021), followed by roles in Asteroid City (2023) and the Netflix short films The Swan and The Rat Catcher.

Friend is director, screenwriter or producer of two award winning short films: The Continuing and Lamentable Saga of the Suicide Brothers (2008) and Steve (2010).

[13][8] Friend played three minor roles in a stage production of The Laramie Project when he was in his third year in drama school, and was spotted by a casting director.

[14] He made his acting debut as Billy Downs opposite Johnny Depp in the 2004 film The Libertine, for which he was named "outstanding new talent" at the 2005 Satellite Awards.

[16] Aged 22, Friend was offered a screen test for the part of James Bond after Pierce Brosnan stepped down from the role.

Graham King, producer of Young Victoria, invited Friend to test for the lead role because he remembered his performance in Pride & Prejudice.

Friend said that the real challenge had been to find a way to portray the darker sides of an essentially good man like Albert, in order to give depth to the character.

[32][33] In 2015, Friend provided narration for Nick Knight's folk horror fashion film, The Face of a Dying Dog.

[34] Friend gained worldwide recognition as CIA operative and assassin Peter Quinn in the acclaimed political thriller series Homeland (2012–2017), his first role in a television-series.

[2] He was offered the lead role in Paul Feig's A Simple Favor, but turned it down to play a funny smaller part in the film instead.

Friend played the role of the mysterious Ernest Donovan in the series Strange Angel from 2018 to 2019; his performance was praised as being 'of amusing weirdness and a creepy-crawly intensity'.

[43] In 2018 Friend performed a new audio drama by John Patrick Shanley, Last Night in the Garden I Saw You, which featured Michelle Williams.

The collaboration started with a cameo appearance as an actor playing a drill-sergeant in The French Dispatch (2021), and continued with a more substantial role in the 2023 film Asteroid City.

[46][47][48] In 2021, after his success portraying a spy in Homeland, Friend was once again mentioned as the possible next James Bond when Daniel Craig gave up the role.

[17] He played a lead role in the 2021 horror film Separation, which got largely negative reviews although Friend's performance as a single father did receive praise.

[51][52] The following year, Friend played network boss Wilson Sikorsy in Tim Kirkby's film Last Looks (2022), which got positive reviews.

[53][54] He starred opposite Sienna Miller and Michelle Dockery as James Whitehouse, a British politician on trial for rape, in the Netflix mini-series Anatomy of a Scandal.

[60] In February 2022, it was announced that Friend would play a lead role in Zack Snyder's science fiction film Rebel Moon; he withdrew from the project because of scheduling problems.

[66] In 2008, Friend and Tom Mison wrote, produced and starred in a short film called The Continuing and Lamentable Saga of the Suicide Brothers.

Plans for Friend to write, direct and star in a feature-length road movie about confidence tricksters called Barton & Charlie & Checco & Bill were mentioned in the media in 2014–2015, but the project did not materialise.