Machete travels to San Antonio, where he meets handler and beauty contestant Blanca Vasquez. At Acapulco he looks for Cereza, who can lead him to Mendez, but is attacked by brothel madam Desdemona, who is Cereza’s mother. As Mendez’s beloved virgin, Cereza warns Machete’s about Mendez’s split personality. As they travel to Mendez’s headquarters, Mendez’s enforcer Zaror receives a call from Mendez, and shoots Cereza.
Machete learns that Mendez has wired the missile’s launch device to his own heart so that if he dies, the missile fires. Mendez kills the device’s designer and activates its 24-hour timer. Killing Zaror along the way, Machete intends to escort Mendez to the US and find a way to disarm the missile. Mendez shares that he is a self-proclaimed secret agent who tried to expose his corrupt superiors, only to be betrayed and forced to watch his wife and family being tortured and killed, causing him to develop the split personality.
As they head to the border, a hit is put on Machete, and the two are targeted by multiple assailants including: Desdemona and her prostitute assassins; a shapeshifting hitman called El/La Camaleón; Doakes and Clebourne; and various locals. Machete and Mendez evade the assilants, only to be caught by a reborn Zaror and the masked mercenaries who killed Sartana. Zaror decapitates Mendez, and Machete is riddled with bullets.