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, The Wrong Door and Ideal series 5 and 6 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. 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.