Since 1996, Myles has appeared in a number of both American and English films and television productions. In 2001, she got a small role as Johnny Depp 's wife, Victoria Abberline, in the thriller film From Hell. She had a supporting role in the 2003 film Underworld and in sequel Underworld: Evolution (in a brief flashback scene). In 2004, she played the schoolgirl lead in the thriller Out of Bounds and she also played Lady Penelope in the Thunderbirds. In 2006, Myles co-starred with actor James Franco in the romantic drama Tristan + Isolde, playing the role of Isolde.

Myles appeared as Madame de Pompadour in a 2006 episode of Doctor Who, "The Girl in the Fireplace". She co-starred opposite English actor Max Minghella, playing his love interest in 2006's quirky comedy Art School Confidential. Also in 2006, Myles appeared in a BBC TV adaptation of Dracula; she played Lucy Westenra alongside Marc Warren, David Suchet and Dan Stevens. As of 2007, she filmed Outlander with James Ca