Harris has appeared in television and film since she was nine, including a stint on the remake of the science fiction series The Tomorrow People. She became internationally well-known in 2002 with her lead performance in Danny Boyle's post-apocalyptic film 28 Days Later, opposite Cillian Murphy. In the same year, she starred in the television adaptation of Zadie Smith's White Teeth.

Since then, Harris has been cast primarily in supporting roles in big budget films, such as Pirates of the Caribbean: Dead Man's Chest, Pirates of the Caribbean: At World's End, and Michael Mann's Miami Vice. She also did a comic turn in Michael Winterbottom's well-regarded indie ensemble piece, Tristram Shandy: A Cock and Bull Story, and will appear with Josh Hartnett in the 2008 release of August. She starred in Channel 4's adaptation of the novel Poppy Shakespeare which was first shown on 31 March 2008.