McGillis, 52, is best known for her roles in "Top Gun," "Witness" and "The Accused."
Her casting in "Stake Land" was announced by Dark Sky Films and Glass Eye Pix.
Written by Jim Mickle and Nick Damici, and directed by Mickle, the film is about what happens after a global spread of vampirism.
McGillis plays a nun who joins a small team of survivors -- played by Damici, Danielle Harris and Conor Paolo -- as they make a treacherous journey north to safety through the war-torn United States.
"Jim and Nick have written a uniquely intense part for Sister, and we are thrilled to see Kelly McGillis in the role. This is a very ambitious project, with a genuinely epic sweep, and we cannot wait to bring it to audiences next year," Dark Sky's Executive Vice President Greg Newman said in a statement.