Danny Trejo (Machete Cortez), Steven Seagal (Rogelio Torrez), Robert De Niro (Senator John McLaughlin), Jessica Alba (Sartana Rivera), Michelle Rodriguez (Luz / Shé), Don Johnson (Von Jackson), Jeff Fahey (Michael Booth), Cheech Marin (Padre Cortez), Lindsay Lohan (April Booth), Stacy Keach (Doc Franklin), Daryl Sabara (Julio), Gilbert Trejo (Jorge), Ara Celi (Reporterin), Tom Savini (Osiris Amanpour), Shea Whigham (Attentäter, Booths Scherge), Jason Douglas (Streifenpolizist), Felix Sabates (Doc Felix), Electra Avellan (Krankenschwester Mona), Elise Avellan (Krankenschwester Lisa), Marci Madison (Krankenschwester Fine), Mayra Leal (Nacktes Mädchen), Juan Gabriel Pareja (Rico), Alicia Rachel Marek (June), Tina Rodriguez (Tristana), Roland Ruiz (Luis), Greg Ingram (Cristos), Billy Blair (Von Jacksons Handlanger), Jim Henry (Wächter), Alejandro Antonio (Chief)