Miller was born in Kingston upon Thames, South West London, England, the son of Anne (née Lee), who worked in theatre production and starred in many films like Lost & Found, and Alan Miller, a stage actor and later a stage manager at the BBC. Miller's maternal grandfather was Bernard Lee, famous for playing the character M in the earlier James Bond films. Miller has stated that he has fond memories of being at Television Centre with his sister and watching Top of the Pops and Blue Peter being made. Miller was educated at Tiffin School in Kingston upon Thames where he gained his first acting experience and played in the Tiffin Swing Band. Miller left school at age 17 to pursue his acting career.

After a stint in EastEnders as Jonathan Hewitt, Miller got his big break in the film Hackers (1995), co-starring Angelina Jolie; the two were married in 1996. In 1997, Miller was involved with the creation and operation of Natural Nylon along with friends Jude Law (whom he met in the National Youth Music Theatre), Sadie Frost, Ewan McGregor, Sean Pertwee, Damon Bryant and Bradley Adams. Natural Nylon folded in 2003.

Aside from EastEnders he has appeared on television in the BBC's modernization of The Canterbury Tales as Artie in The Pardoner's Tale and as Lord Byron in a BBC production about the life of the poet. He worked on the US television series Smith (CBS, Fall 2006). His first appearance on US Television was the 1996 miniseries Dead Man's Walk.

Shortly after Hackers, Miller was cast in Trainspotting (1996), which gained him renown. He was suggested for the role of Sick Boy by Ewan McGregor. The accent he used in the film was so convincing that it led many people[citation needed] to erroneously believe he was Scottish. In 1997, he played Billy Prior in the film adaptation of Pat Barker's World War I novel, Regeneration, and in 2000 he played the role of Cameron Colley in Complicity (video title Retribution), based on the book by Iain Banks. Also in 2000, he appeared as Simon Sheppard in Wes Craven's Dracula 2000.

In 2005, he was considered for the role of James Bond, to replace Pierce Brosnan. The role went to Daniel Craig. The following year, Miller portrayed cyclist Graeme Obree in The Flying Scotsman. In 2007, Miller was selected to play the lead role in a new series for ABC, called Eli Stone; the series was cancelled after two seasons. The first season had been interrupted by a lengthy writers' strike.

He was considered as a third team-mate to join Ben Fogle and James Cracknell in Team QinetiQ for the Amundsen Omega 3 South Pole Race (January 2009). He participated in training for the event in Norway which was televised for a BBC2 documentary series On Thin Ice. He was not able to attend the race due to filming commitments created by television programme Eli Stone being extended for a second season.

In 2009 he played Mr. Knightley in a BBC adaptation of Jane Austen's Emma. He also appeared on Broadway with Sienna Miller in a production of "After Miss Julie", his performance receiving generally excellent reviews.

In early 2010, a rumour was floated that Miller was in talks to portray Rick Grimes in the Frank Darabont film adaptation of the comic The Walking Dead. but the part went to Andrew Lincoln. On 25 June 2010, he earned a guest role in the fifth season of Dexter.

Miller married actress Angelina Jolie on 28 March 1996. They separated eighteen months later and were divorced on 9 February 1999. He began dating actress/model Michele Hicks in 2006. Miller and Hicks married in Malibu in July 2008. Their son, Buster Timothy Miller, was born December 3, 2008 in Los Angeles, California, United States.

Miller is a supporter of Chelsea FC. He is a marathon runner, often supporting the charity Mencap. He ran the 2008 London Marathon in 3:01:40. Miller was signed up to run the 2006 Marathon des Sables but had to drop out due to contractual obligation to the television series Smith, which was cancelled after three episodes.