Natali's directing debut came in 1997, when he was approached to direct Cube (1997). The film became a success worldwide, especially in Japan and France, grossing $15 million in France, and breaking box office records for a Canadian film. At the 19th Genie Awards, the film received five nominations and also won the award for Best Canadian First Feature at the Toronto International Film Festival. After this success, Natali went on to direct Cypher (2002) and Nothing (2003).
Following the June 2010 release of Splice (2009), Natali's next efforts were expected to be an adaptation of J. G. Ballard's 1975 novel High Rise and a 3D adaptation of the Len Wein/Berni Wrightson comic book character Swamp Thing, for producer Joel Silver. A May 2010 item in The Hollywood Reporter, however, announced that Natali was to replace Joseph Khan as director of the highly anticipated adaptation of cyberpunk author William Gibson's 1984 masterwork Neuromancer. Natali is nominated for the 4th Annual Splatcademy Awards under the category "Best Director" presented by Cadaver Lab for his work Splice. In 2013 his series Darknet, an adaptation of the Japanese series Tori Hada, began airing on Super Channel in Canada. In 2014, he directed the episodes "Su-zakana" and "Naka-choko" of the second season of the crime drama series Hannibal and in 2015 the episodes "Antipasto", "Primavera" and "Secondo" of the third season of the same TV series. in 2015, he also directed the second episode (entitled "Simon") of the first season of the American supernatural drama television series The Returned.
^Riser, Troy (21 October 2005). "Interview: Vincenzo Natali: Turtles All The Way Down". the-trades.com. The Trades. Retrieved 10 April 2011. There really weren't too many touchstones, literary or otherwise. Except Beckett. We do owe a small debt to the Theatre of the Absurd." "Yes. He's a huge influence. But we're very different kinds of directors.
^Stubbs, Phil (2005). "Vincenzo Natali on the making of Tideland". smart.co.uk. Dreams – The Terry Gilliam Fanzine. Retrieved 10 April 2011. Yes I have a new film called Nothing - which is a title that causes endless confusion. It was just released in Canada a few months ago. If there is a single film that I've done that owes a real debt to Terry, that's it actually.