Despite being born in Detroit, Michigan, Natali moved to Toronto at a very young age. He began his career working on animated TV series such as Beetlejuice, and Fievel's American Tales as a storyboard artist, a role in which he also worked on the 2000 feature film Ginger Snaps, directed by John Fawcett.
Following from his directorial debut on the short film Elevated (co-written with Karen Walton) in 1996, Natali directed his first feature, the scie-fi indie film Cube. Featuring seven characters trapped in a maze of identical rooms, the film won nunmerous awards from various international film festivals, including the Best Ontario Feature at Cinéfest Sudbury. Cube was also co-written by Orphan Black co-creator Graeme Manson, and starred Julian Richings. A sequel, Cube 2: Hypercube, and prequel, Cube Zero were also released, although Natali had no involvement with either.
Despite the success of Cube, Natali's next feature wouldn't be released until five years later, 2002's Cypher. Natali also wrote and directed Nothing, and Splice, and in 2013 directed Haunter. He also diected segments of the anthology films Paris, je t'aime, and ABC's of Death 2, as well as the documentary Getting Gilliam.
Natali has also directed episodes for a number of TV series, beginning in the late 90s with PSI Factor: Chronicles of the Paranormal, and Earth: Final Conflict. More recently he has also directed episodes of the television series Hannibal, and The Returned, and Wayward Pines. It has also been announced that he wil direct episodes of the forthcoming series American Gods, and Star Trek: Destiny.