Knucklehead follows the on-the-road adventures of a trio of misfits -- a naïve giant and church orphan-turned-amateur fighter Walter Krunk (Big Show); former mixed martial arts champion-turned-manager Eddie Sullivan (Mark Feuerstein); and church aide-turned-chaperone, Mary O'Connor (Melora Hardin) -- fighting their way across the south to the annual Pro-Am mixed martial arts tournament in New Orleans.