Highmore began with small parts on TV at the age of 7. In two movies Highmore played with members of his family. His brother Bertie played his brother in Women Talking Dirty. Also his father Edward played the father in "Jack and the Beanstalk: The Real Story."

In 2004, he had a breakthrough with his critically acclaimed performance as troubled Peter Llewelyn Davies in "Finding Neverland." Highmore received several nominations and awards for the role, including a Broadcast Film Critics Award and a Screen Actors Guild Award nomination. In 2005, he played the part of the hard-working Charlie Bucket in "Charlie and the Chocolate Factory" (adapted from the book by Roald Dahl). He was reportedly recommended for the role by the film's star Johnny Depp, who starred in "Finding Neverland" and was impressed by the young actor's performance.

Highmore next appeared as the title character in "August Rush" with Keri Russell, Jonathan Rhys Meyers and Robin Williams. The story is about a musical prodigy and his journey to find his parents after they are separated at his birth. This movie received a wide release on November 21, 2007. He starred in "The Spiderwick Chronicles," based on the popular children's stories, released in the United States in February 2008. He played American twins Simon and Jared Grace, alongside Sarah Bolger as their sister Mallory Grace.

He took the main role in "Toast," a BBC autobiographical film about Nigel Slater, the chef, which was shown on Thursday, December 30, 2010. He also starred alongside Emma Roberts in 2011's romantic comedy "The Art of Getting By."