The show's original 16 episodes will feature on the DVD, as well as extras including an extended pilot version, commentaries, featurettes, bloopers, a gag reel and deleted scenes.
The comedy, which first aired in 2000 on Fox, ended after 151 episodes in 2006. It won a Peabody Award, seven Emmys and a Grammy Award over its seven-season run.
The DVD will be released on September 24 through Fabulous Films, with a recommended retail price of £29.99.
Malcolm in the Middle starred Frankie Muniz as a boy with a genius IQ attempting to cope with his eccentric family, including dad Hal (Breaking Bad's Bryan Cranston) and mum Lois (Jane Kaczmarek).
Other extras on the new release include featurettes 'A Stroke of Genius' and 'Dewey's Day Job - a portrait of Erik Per Sullivan', four alternate show openings, promotional TV spots, episode synopses, and a behind-the-scenes preview of season two.
Watch the music for Malcolm in the Middle theme song 'Boss of Me' by They Might Be Giants below: