Born in Leeds, Lewis made his acting debut in Some Kind of Life (1995), guest-starring on dramas for ITV and BBC One before appearing in Harry Potter and the Philosopher's Stone (2001).

Lewis played the role for ten years, concluding with the final film, Harry Potter and the Deathly Hallows – Part 2 (2011), for which he received critical praise.

Lewis starred in The Rise (2012) which premiered at the Toronto International Film Festival to positive reviews and made appearances on BBC dramas Bluestone 42 and Death in Paradise in 2013 and 2015, respectively.

Lewis, a fan of the series, initially attended an open audition at the Queens Hotel, Leeds, before being contacted two months later to perform a screen test for director Chris Columbus, eventually earning the role of Neville Longbottom.

[11] For the role, Lewis wore a set of false teeth, shoes two sizes too big, a fat suit and ear prosthetics.

During filming, co-star Helena Bonham Carter accidentally ruptured Lewis' eardrum when she stuck her wand in his ear during a scene.

His performance was praised by critics for his "scene stealing potential"; CTV News referred to Lewis as a "breakout stud" and "man of action".

[22][23] Harry Potter author J. K. Rowling gave a speech at the premiere of Deathly Hallows – Part 2 in London, where she stated that there were seven major cast members in the series, whom she referred to as "The Big Seven" (Daniel Radcliffe, Rupert Grint, Emma Watson, Tom Felton, Lewis, Evanna Lynch and Bonnie Wright).

[35][36] He starred alongside Niamh Cusack in the London premiere of Unfaithful, written by playwright Owen McCafferty, from August to October 2016.

[40] In 2018, he starred on the ITV drama Girlfriends, written by Mellor,[41] and appeared in the 2018 neo-noir Terminal, which premiered at the Edinburgh International Film Festival to negative reviews.

[43] Lewis appeared in the Yorkshire-set television series All Creatures Great and Small, which aired on Channel 5 in 2020 to high ratings and critical acclaim.