Lewis was born in Leeds, West Yorkshire, England, to Adrian and Lynda Lewis. He has two older brothers, Chris Lewis, a television editor, and Anthony Lewis, an actor and musician.

Matthew has been acting since he was five years old. He started off with minor parts in television programs and then tried out for the part of Neville Longbottom. He has portrayed Neville Longbottom in the first five Harry Potter films. For his role as Neville, Matthew wears yellow and crooked false teeth, two-sizes-too-big shoes and has plastic bits placed behind his ears in order to make them stick out more. This is done to give the character a more clownish look.