Vo filme Dvanásť opíc hrajú Bruce Willis (James Cole), Madeleine Stowe (Dr. Kathryn Railly), Brad Pitt (Jeffrey Goines), Christopher Plummer (Dr. Goines), David Morse (Dr. Peters), Jon Seda (Jose), Christopher Meloni (Lt. Halperin), Joey Perillo (Detective Franki), LisaGay Hamilton (Teddy), Matt Ross (Bee), Annie Golden (Woman Cabbie), Michael Chance (Scarface), H. Michael Walls (Botanist), Bob Adrian (Geologist), Bill Raymond (Microbiologist), Ernest Abuba (Engineer), Nell Johnson (Ward Nurse), Rozwill Young (Billings), Joseph Melito (Young Cole), Frank Gorshin (Dr. Fletcher), Aaron Michael Lacey (WWI Sergeant), Vernon Campbell (Tiny), Simon Jones (Zoologist), Carol Florence (Astrophysicist / Jones), Irma St. Paule (Poet), Frederick Strother (L.J. Washington), Charles Techman (Professor), Rick Warner (Dr. Casey), Anthony 'Chip' Brienza (Dr. Goodin), Bruce Kirkpatrick (Policeman No. 1), Wilfred Williams (Policeman No. 2), Joilet Harris (Harassed Mother), Drucie McDaniel (Waltzing Woman Patient), John Blaisse (Old Man Patient), Louis Lippa (Patient at Gate), Stan Kang (X-Ray Doctor), Pat Dias (WWI Captain), Felix Pire (Fale), Karl Warren (Pompous Man), Joseph McKenna (Wallace), Stephen Bridgewater (Airport Detective), Ray Huffman (Plump Businessman), Charley Scalies (Impatient Traveler), Paul Meshejian (Detective Dalva), Kevin Thigpen (Kweskin), Jann Ellis (Marilou), Michael Ryan Segal (Weller), Korchenko (Thug No. 1), Robert O'Neill (Wayne), Harry O'Toole (Louie / Raspy Voice), Chuck Jeffreys (Thug No. 2), Barry Price (Agent No. 1), John Panzarella (Agent No. 2), Janet Zappala (Anchorwoman), Lisa Talerico (Ticket Agent), Tiffany Baldwin (Student in Airport (uncredited)), C.J. Byrnes (Psychiatric Patient (uncredited)), Tom Detrik (FBI Agent (uncredited)), Joe Gerety (Sprayer (uncredited)), Bonnie Loev (Time Portal Nurse (uncredited)), Raymond Mamrak (Travler (uncredited)), Allelon Ruggiero (Inpatient (uncredited)), Thang (Monkey Member (uncredited)), Sal Mazzotta (Prisoner Joey (uncredited)), Bart the Bear (Bear), Donald Faison (Psychiatric Prisoner (uncredited)), Richard Stanley (Man in Transit Lounge (uncredited)).