In 2006 Wheatley won a “Lion” award at Cannes advertising festival for directing the AMBX viral, with The Viral Factory. In July 2006 he directed live-action sections of the TV series Modern Toss, (“i live ere”, “Alan”, “Drive by abuser”, “Customer services”, “Accident and emergency”, “Citizens advice”, “Illegal alphabet”), which was aired on Channel 4. Wheatley has also written and created clips for BBC Two’s Time Trumpet and has appeared in and directed sketches for BBC Three’s Comedy Shuffle. Between 2007 and 2009 Wheatley directed series 2 of Modern Toss and Ideal series 5 and 6. In 2008, Wheatley co-created and directed the sketch series The Wrong Door for BBC Three.

In May 2009 he directed the feature film Down Terrace in eight days; it won the Next Wave prize at Fantastic Fest in Austin and Best UK Feature at Raindance in London. In 2010 Wheatley completed his second feature, Kill List for Warp X. The film received critical acclaim and won Michael Smiley a British Independent Film Award for Best Supporting Actor. The movie holds a 76% rating on Rotten Tomatoes with a critic consensus describing the film as “an expertly executed slow-burn crime thriller that thrives on tension before morphing into visceral horror.”

Wheatley’s third film was the black comedy Sightseers, released in the UK in November 2012. It was written by its stars, Alice Lowe and Steve Oram, with additional material by Amy Jump, and was chosen for the Directors’ Fortnight section of the 2012 Cannes Film Festival. Wheatley’s fourth film, A Field in England was financed through the Film4 talent and ideas hub, Film4.0. It was followed in 2016 by High Rise, an adaptation of the J.G. Ballard novel of the same name. He has also directed advertisements for Blink Productions and Moxie.

A sci-fi TV series, Silk Road, written and directed by Wheatley, has been announced. It is said to be “in the vein of the Patrick McGoohan TV series The Prisoner,” and will be screened on HBO. In 2014, Wheatley directed the first two episodes of the eighth series of Doctor Who, a show he has been a fan of since childhood.

In November 2018, Wheatley was announced as the director of a new adaptation of Daphne du Maurier’s gothic romance novel Rebecca, a Working Title Films production to be released on Netflix. The film will star Lily James, Armie Hammer, and Kristin Scott Thomas. The film received mixed reviews upon its release in October 2020, with a score of 46 on review aggregator site Metacritic.

In the fall of 2019, Wheatley was announced as the director of Tomb Raider 2, based on the popular video-game franchise of the same name and starring Academy Award-winning actress Alicia Vikander. However, in October 2020 it was announced that the film’s March 2021 release had been delayed indefinitely amid a series of production issues related to the COVID-19 pandemic.

In October 2020, it was announced that Wheatley would take over the sequel to the science-fiction horror film The Meg, starring Jason Statham and Li Bingbing, based on Steve Alten’s eponymous series of novels. The author himself confirmed the sequel film will be an adaptation of the second book of the series, The Trench.

In November 2020, it was announced that Wheatley had wrapped production on In the Earth, a pandemic-set horror film starring Joel Fry, Ellora Torchia, Hayley Squires and Reece Shearsmith. Neon plans to distribute the film in the U.S. in 2021.