The vampire women of Mexico have awakened to take their revenge on the descendant of the man who destroyed them shortly after they had emigrated to Mexico during the 19th century.

Agent Joaquin recalls his latest mission while lying wounded in an ambulance: Joaquin has infiltrated into a band of smugglers. When the villains learn the truth about him, they kidnap Jouqin's fiancee. Santo comes to her rescue and fights the band.

Dr. Frankenstein and her assistant, Dr. Yanco, are going to bring one of their experiments to life in Santo Vs. Frankenstein's Daughter. She intends to use a monster named Ursus to do her evil bidding. Using a youth serum to retain their vitality, the doctors set their sights upon none other than El Santo. They need his super human blood to regenerate a stronger youth serum. They kidnap Santo's goddaughter, Norma and lure him into Dr. Frankenstein's lab where he is captured and enslaved. Will Santo make it out alive?