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Farrell began acting in the BBC drama series Ballykissangel (1998) and made his film debut in the drama The War Zone (1999). His first lead film role was in the war drama Tigerland (2000), and he made his breakthrough in Steven Spielberg's science fiction film Minority Report (2002). He took on high-profile roles such as Bullseye in Daredevil (2003) and as Alexander the Great in Alexander (2004), with further starring roles in Michael Mann's Miami Vice (2006) and Woody Allen's Cassandra's Dream (2007).

Farrell earned acclaim for playing a novice hitman in his first film with frequent collaborator Martin McDonagh, the dark comedy In Bruges (2008), winning a Golden Globe Award. He went on to play a variety of leading and character roles in the comedy Horrible Bosses (2011), the science fiction film Total Recall (2012), the drama Saving Mr. Banks (2013), the dark comedies Seven Psychopaths (2012) and The Lobster (2015), the thrillers The Killing of a Sacred Deer (2017), The Beguiled (2017), and Widows (2018), and the fantasy films Fantastic Beasts and Where to Find Them (2016) and Dumbo (2019). He also starred in the second season of HBO's thriller series True Detective (2015).

Farrell played Oz Cobb/Penguin in the superhero film The Batman (2022) and the HBO series The Penguin (2024), winning a Golden Globe award for the latter. In 2022, he gained acclaim for his roles in the science fiction drama After Yang, the survival film Thirteen Lives, and McDonagh's drama The Banshees of Inisherin. For playing a naïve Irishman in the lattermost, he won the Volpi Cup for Best Actor and another Golden Globe, in addition to a nomination for the Academy Award for Best Actor.