Spall, third of four sons, was born in Battersea, London; his father, Joe, was a postal worker, and his mother, Sylvia, a hairdresser. He trained at the National Youth Theatre and RADA, where he was awarded the Bancroft Gold Medal as the most promising actor in his year. His brother, Matthew, is studio director of the computer games company Morpheme.

Initially notable in the UK for playing the gormless Barry Taylor in all four series of Auf Wiedersehen, Pet he has since starred in films such as Secrets & Lies, Shooting the Past, Rock Star, The Last Samurai, and Lemony Snicket's A Series of Unfortunate Events.

He gained international recognition as Peter Pettigrew ("Wormtail") in Harry Potter and the Prisoner of Azkaban, Harry Potter and the Goblet of Fire and Harry Potter and the Half-Blood Prince.

Spall played the starring role of Albert Pierrepoint in the 2005 film Pierrepoint, which was released as The Last Hangman in the United States. In the 2006 video game Grand Theft Auto: Vice City Stories, Spall voiced Phil Collins' manager, Barry Mickelthwaite.

In 2007, he starred as Nathaniel in Disney's Enchanted and Beadle Bamford in Tim Burton's production of Sweeney Todd.

On 31 December 1999, he was named an Officer of the British Empire.