Spall performed in Secrets & Lies (1996), and was nominated for the BAFTA Award for Best Actor in a Leading Role. Subsequently, he starred in many films, including Hamlet (1996), Still Crazy (1998), Nicholas Nickleby (2002), The Last Samurai (2003), Enchanted (2007), Sweeney Todd: The Demon Barber of Fleet Street (2007), The Damned United (2009), The King's Speech (2010), Ginger and Rosa (2012), Denial (2016), and The Party (2017). He voiced Nick, a cynical, portly rat in Chicken Run (2000). He played Peter Pettigrew in five Harry Potter films, from Prisoner of Azkaban (2004) to Deathly Hallows – Part 1 (2010).

Spall has collaborated with director Mike Leigh, making six films together: Home Sweet Home (1982), Life is Sweet (1990), Secrets & Lies (1996), Topsy-Turvy (1999), All or Nothing (2002), and Mr. Turner (2014). Spall won great acclaim for his performance in the last of these for his portrayal as J. M. W. Turner winning him the Best Actor Award at the 2014 Cannes Film Festival.

He starred in the television documentary Timothy Spall: ...at Sea (2010–2012) and in 2019 he appeared as Lord Arthur Wallington in the 6-part BBC Cold War drama Summer of Rockets.