Spall studied at the Royal Academy of Dramatic Art (RADA), where he earned the school's prestigious Bancroft Gold Medal, then headed for the stage. Among his many successes were his performances as Bottom in the controversial Royal National Theatre production of "A Midsummer Night's Dream", directed by Robert Lepage, and as Wackford Squeers in Trevor Nunn's production of "Nicholas Nickleby" at the Royal Shakespeare Company. But British audiences know him best from his television work, which included the early-80’s sitcom "Auf Wiedersehen Pet", and mid-90’s sitcom "Outside Edge", opposite Brenda Blethyn, who played his sister in "Secrets & Lies". American audiences saw him on the 1993 HBO special "Tracey Ullman: A Class Act", and as guest a star on "Young Indiana Jones Chronicles" (ABC, 1992).

Spall's feature film appearances have consisted of supporting roles, but he has worked with some of the most important directors of the past two decades. One of his earliest film appearances was in the little-seen "The Life Story of Baal" (1978). Another early role was as a projectionist in Franc Roddam's "Quadrophenia" (1979), the rock-n-roll opera written by The Who’s Pete Townshend. Roles became larger in the mid-80s after Spall's exposure on television. Ken Russell cast him in "Gothic" (1986) as Dr John Polidori, while Agnieszka Holland put him in "To Kill a Priest" (1988). In 1990, Spall was among the cast-within-a-cast of Clint Eastwood's "White Hunter, Black Heart". Also that year, Spall had the meaty film role of Eric Lyle, the sinister chap who steals John Malkovich's passport in Bernardo Bertolucci's "The Sheltering Sky".

Spall was also seen as the foppish yet evil Rosencrantz in Kenneth Branagh's all-star "Hamlet" (1996). He reunited with Branagh in 2000, playing a comical Don Armado in "Love's Labour's Lost". Spall enjoyed a career as an character actor who would always bring something fresh and surprising to his roles, both in British productions—including the winning rock group reuniting comedy "Still Crazy" (1998) as David 'Beano' Baggot, in Leigh's much-heralded Gilbert & Sullivan biopic "Topsy-Turvy" (1999) as 'Dickie' Temple, as a voice in the UK-animated, DreamWorks-produced "Chicken Run" and in Peter Cattaneo's prisonbreak comedy "Lucky Break" (2001)—as well as in American films such as "Rock Star" (2001) and "Vanilla Sky" (2001).

In 2002 Spall enjoyed another outing with Leigh in the bleak but affecting "All or Nothing", playing part of a couple who must experience tragedy in order to rekindle their fading love. Spall shined as Charles Cheeryble for a production of "Nicholas Nickleby", and was part of the ensemble of HBO's much-honored telepic "My House In Umbria" (2003) opposite Maggie Smith and Chris Cooper. His highest-profile role in a major American release came with "The Last Samurai" (2003), in which Spall played the British diplomatic interpreter Simon Graham, who befriends an alcoholic Army captain (Tom Cruise) on his way to Japan to teach Western warfare. Children and booklovers embraced the actor when he took on the role of Peter Pettigrew for "Harry Potter and the Prisoner of Azkaban" (2003), the third sequel in the beloved film franchise, directed by Mexican filmmaker Alfonso Cuaron. Continuing the trend, Spall appeared as Mr. Poe in “Lemony Snicket’s A Series of Unfortunate Events” (2004), an adaptation of the popular children’s book series, starring Jim Carrey as the dastardly Count Olaf.