After being discovered in junior high school, Epps starred in the low budget, short film Gowanus, Brooklyn alongside Matt Kerr, playing the role of "Drey", a high school student. The short film won the Short Filmmaking Award at "Sundance Film Festival" in 2004.
For Half Nelson, Epps won the Gotham Award for Breakthrough Performance (2006); was named Best Supporting Actress by the Boston Society of Film Critics Awards (2006); won the WFCC Award for Female Rights To Male Roles in Movies at the Women Film Critics Circle Awards (2006); and Best Female lead by the Independent Spirit Awards (2007).
In 2007, Epps appeared in the Noah Buschel film Neal Cassady about Neal Cassady and his alter ego Dean Moriarty, playing the role Annie Gibson. In the same year, Epps also acted in Aliens vs. Predator: Requiem although her portrayal of Kendra was completely omitted from the theatrical as well as the DVD release.
Epps made her first TV appearance in an episode of Law & Order: Special Victims Unit airing on April 15, 2008, titled "Undercover" as Ashley Tyler. In 2013 she starred in American Milkshake alongside Tyler Ross and Georgia Ford.
In 2009, Shareeka provided spoken word vocals on the songs "Intro" and "Werewolf Heart" from Dead Man's Bones eponymous debut album. Ryan Gosling, who co-starred in Half Nelson, is one of the two members of Dead Man's Bones.
