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Macdonald made her film debut in Danny Boyle's Trainspotting (1996). She was nominated for the BAFTA Award for Best Actress in a Supporting Role for her role in the Coen brothers film No Country for Old Men (2007). During her career, she has taken roles in  Elizabeth (1998), Gosford Park (2001), Intermission (2003), Nanny McPhee (2005),  Harry Potter and the Deathly Hallows – Part 2 (2011), Anna Karenina(2012), T2 Trainspotting (2017), and Operation Mincemeat (2021). She voiced Princess Merida in the Disney Pixar animated Brave (2012).

On television, she won the Primetime Emmy Award for Outstanding Supporting Actress in a Miniseries or a Movie for her role in the BBC One film The Girl in the Cafe (2005). She was further Emmy-nominated for portraying Margaret Thompson in the period crime drama series Boardwalk Empire (2010–2014). She also acted in Black Mirror's Hated in the Nation (2016), the limited series Giri/Haji (2019), and Line of Duty(2021).