The Paramount Pictures film will feature Hirsch as Christopher McCandless, who dropped out of society after graduating from college and went to live the wilderness of Alaska, The Hollywood Reporter said.
Four months after arriving, McCandless was found dead in an abandoned bus near his campsite, The Reporter said. The screenplay was adapted by Penn from "Into the Wild" by Jon Krakauer.
Keener will play a woman who picks up McCandless while hitchhiking and takes him in as a surrogate son while Vaughn will portray a tow-truck driver he meets along the road.
Keener was recently nominated for an Oscar for her work in "Capote" and was earlier nominated for her role in "Being John Malkovich." Vaughn next appears with girlfriend Jennifer Aniston in "The Break Up."