Sewell made his film debut as a junkie in the 1991 film Twenty-One but first made a real impact on television, as Ladislaw in MiddleMarch and Seth Starkadder in Cold Comfort Farm. More film work followed, as part of the all-star cast in Kenneth Branagh's Hamlet (as Fortinbras) and as a leading man in Dangerous Beauty, Dark City (opposite Jennifer Connelly), and In a Savage Land.
He played a variety of Hollywood villains and cads, in Bless the Child, A Knight's Tale, The Legend of Zorro, and The Illusionist. He also appeared in Tristan + Isolde and Amaxing Grace. In 2008, he played Alexander Hamilton opposite Paul Giamatti in the HBO miniseries John Adams.