Her breakthrough role was as Nola, a prostitute in Memphis, Tennessee, in the 2005 film "Hustle & Flow". Director Craig Brewer saw Manning's picture in a photography book and was convinced that the actress who played Nola should look just like her. Subsequent film roles include "Unbeatable Harold" and "When the Nines Roll Over". Followed by "Weirdsville", co-starring Scott Speedman and Wes Bentley. Boomkat's song "It's Not My Fault" appeared on the soundtrack for the film as a duet by Manning and John Rowley. In 2007, she played Ivy Chitty on the short-lived Fox television series "Drive". In "After Sex" Manning played the supporting role of Alanna. She had leading roles in horror films "Cult" and "Banshee"; in the latter, she performed her own stunts. "I got hurt one day during one of the chase scenes, where another car crashed into my car," Manning explained of her stunts. Manning appeared in the romantic comedy "Jack and Jill vs. the World". She played Rita Cherry on four episodes of "Sons of Anarchy." In 2008 she appeared in Butch Walker's music video for "The Weight Of Her" and in will.i.am's collage-style music video, "Yes We Can". She co-starred with Bill Pullman in the surreal drama film "Your Name Here", in which she played Nikki, who is based on Victoria Principal. The film is based loosely on sci-fi writer Philip K. Dick's life.