Santo and Blue Demon vs. Dr. Frankenstein aka Santo y Blue Demon contra el doctor Frankenstein begins with a woman walking home from work who is kidnapped by a muscular black man who walks in a stiff, robot-like manner. She is taken to the secret laboratory of Dr. Irving Frankenstein. Frankenstein and his assistant Molina try to transplant the brain of the woman into the skull of another woman, and vice versa. But the operation fails, and both die. But instead of disposing of the bodies secretly, Frankenstein reanimates them and sends them out into the street. The women, wearing hospital gowns, their heads wrapped in bloody bandages and with black circles around their eyes, go to their homes: one strangles her sister, the other kills her husband.
Frankenstein, who is really 113 years old but looks young, is experimenting on brain transplants so he can revive his wife Sandra, who died of brain cancer 80 years before. Molina brings two aged scientists to help: Frankenstein gives them a dose of the serum that restores their youth, and they agree to help him.
Frankenstein’s only success is the black zombie Golem, who is motivated by an electronic device planted in his brain. But Golem, although immensely strong, is clumsy and slow. Frankenstein wants Santo’s brain for his next experiment. He decides to kidnap Alicia Robles, a young woman whose father was a professional wrestler and who is now close friends with Santo and Blue Demon. Alicia is snatched when she leaves work, and Golem kills several policemen who try to intervene.
Santo and Blue Demon are notified of the kidnaping. Cmdte. Gutiérrez of the police welcomes their assistance; he has also assigned two women detectives, Marta and Carmen, to the case. When Frankenstein reads about this, he’s upset: “Police wearing pants don’t worry me, but police wearing skirts make me nervous. I’ve never trusted feminine intuition.” He sends his henchmen to kidnap the two women, but Santo and Blue Demon foil the attempt. However, Golem arrives and the two wrestlers realize that discretion is the better part of valor, and duck out the back way with the two female detectives.
Frankenstein sends a note to Santo: he’ll release Alicia if Santo surrenders in her place. Santo gives Blue Demon a wristwatch that contains a receiver; he has the transmitter in his watch, in case things get dangerous. Santo goes along with Frankenstein’s men willingly, but the mad doctor refuses to release Alicia. Santo is strapped to an operating table in preparation for the experiment. He activates the watch, and Blue Demon arrives to release him. They defeat Frankenstein’s men and free Alicia. However, Frankenstein, his chief henchman, and Golem escape.
In order to get revenge, Frankenstein poses as a foreign (masked) wrestling promoter, with Golem as his (masked) wrestler named “Mortis.” He wrestles Santo, and is strangling the silver-masked man when Blue Demon spots Frankenstein’s aide in the audience. He forces the man to reveal the plot. Frankenstein summons Golem from the ring, and they flee to the catwalks high in the arena. Blue Demon and Santo pursue: Golem and Frankenstein fall to their deaths. Frankenstein’s corpse rapidly ages after he dies.