The comic duo join Hugh Bonneville in the show, which is being shot in SD and 3D.
Smith and Vegas will play the mum and dad of lonely 12-year-old Chloe (Nell Tiger Free), who becomes close friends with tramp Mr Stink (Bonneville).
Mrs Biggs star Smith said: "David is such a brilliant writer, and the character just jumped off the page when I read it. I can't wait to work with Hugh and Johnny."
Harish Patel (Coronation Street, Run Fat Boy Run) will play Chloe's newsagent friend Raj.
Britain's Got Talent judge Walliams will also appear as the Prime Minister.
Mr Stink is Walliams's second children's novel. It was first published in 2009 and has since sold over 250,000 copies.
