Santo and Blue Demon vs. Dracula and the Wolf Man aka Santo y Blue Demon contra Drácula y el Hombre Lobo begins with a wrestling match between Santo and Angel Blanco. Meanwhile, in an underground chamber the hunchbacked Eric invokes the Prince of Darkness. Seven eclipses of the sun and moon have occurred since the Magician Cristaldi slew Drácula and the Wolf Man. Soon they will rise again.
Santo and his girlfriend Lina go to visit her uncle, Professor Luis Cristaldi, who lives on the outskirts of the city with his widowed daughter Laura, and Laura’s little girl Rosita. The Professor received a letter indicating that the Cristaldi family is going to have a terrible vengeance wreaked on them. 400 years before, his ancestor killed Drácula and the Wolf Man with a magic dagger–which the Professor now possesses. Santo promises to help Laura, Lina and Rosita if anything happens to the older man.
Later, the Professor puts the dagger in Rosita’s bedroom to protect her. However, as he returns to his own room, he is chloroformed and dragged off by Eric, who takes him to the underground chamber. Eric’s ancestors served Drácula and now he will do his part. The Professor warns Eric that Drácula can’t be trusted. “I don’t want his gratitude,” Eric replies, “I want his gold!” He hangs Cristaldi upside-down and slits his throat, allowing the blood to drip into Drácula’s coffin. The vampire changes from a skeleton back into the fully-clad undead Count, and Eric repeats the process on the Wolf Man, who emerges wearing a nice yellow silk shirt.
Drácula tells his servants that they need a legion of vampires and werewolves to begin their quest to dominate the world. In a short period of time, the cave is filled up with men and women prisoners, who are vampirized and werewolf-ized.
Meanwhile, Professor Cristaldi’s absence is reported to the police, who aren’t too enthusiastic about hunting for a vampire and a werewolf. So, Santo tells Lina and Laura that he’s going to ask “a faithful and brave friend, a formidable ally” to help out. Laura: “Who is he?” There is a cut to the wrestling ring, and the announcer introduces “Blue Demon!”
After Blue defeats Renato el Hippie, Santo visits him in his dressing room. “Once more we’ll fight together for justice,” Santo says. Blue digs his wristwatch-radio out of his locker, just in case.
The Wolf Man, now clean-shaven, is taken to an apartment in the city by Eric. Dressed up in a suit, he’s quite presentable: “You look good, boss,” Eric says. “Yes, very good,” Rufus admits. He then has some gangsters in Eric’s employ attempt to kidnap Laura, so that he can “rescue” her. She falls for his smooth talk. Later, Rufus tells Drácula: “She’s a sad and romantic woman. She’ll fall in love with me and we’ll sacrifice her at the next full moon.”
Drácula tries to do his bit, with Rosita as his intended target, but recoils when he spots the magic dagger on her nightstand. He’ll have to find some way around it.
Rufus pays a visit to Laura’s house; when he leaves, Blue Demon follows. He climbs a tree to spy on Rufus in his apartment, but Eric spots the masked wrestler in a mirror, and he and Rufus pretend that Rufus is trying to help free the “kidnaped” Professor Cristaldi. Santo and Blue Demon follow Eric to a warehouse, where the gangsters attack them. However, Lina has stowed away in Santo’s car, and she saves the wrestlers by toppling a wall of boxes with a forklift! She also calls the cops, who arrive and arrest the crooks.
Rufus, still pretending to help, says he has learned that Cristaldi can be found in an old house in the country. Santo and Blue Demon go to check; Santo goes in first, and he does see the white-faced Professor, who starts to strangle him! Eric clubs Santo from behind, but has to leave when Blue Demon enters.
Back at the Cristaldi mansion, the monsters are working overtime. First Rufus and Laura go out for a walk; as described above, a shot of the full moon is followed by a woman’s screams. One down. Then some bald guy vampire bites Josefina, the maid, who lures Rosita out of range of the magic dagger, and they head for the monsters’ hideout in the forest.
Drácula then hypnotizes Lina at long-range and orders her to come to the spook headquarters. Three down. In the meantime, Santo and Blue Demon have returned from their search for the Professor and are passing the time playing chess.
Santo decides to look over some books in the Professor’s library to see if he can find a clue; while he’s reading, Blue Demon sees Lina leave, and he follows her, but is grabbed by three werewolves in the forest.
Santo sees something in a book about the magic dagger, and remembers his original conversation with the Professor. He finds the dagger in Rosita’s room, but suddenly discovers that everybody has disappeared!
The gardener shows up and says he saw everybody wander off into the forest. Santo uses his wrist-radio to contact Blue Demon, who’s chained up in the vampire’s lair. He gives Santo instructions on how to get there: the cavern is located underneath an old house in the forest.
In that house, Lina is taken to a bedroom by two vampire women. Drácula starts to bite her, but is interrupted by Eric, who reports that Santo is on his way. Rosita, meanwhile, sees her zombie grandfather. Laura, now a red-clad vampire herself, takes Rosita down to the cavern. Santo busts into the house but is gassed by Eric, who starts to stab him with the magic dagger, but changes his mind and goes to see Lina instead. He thinks maybe Lina knows how to “operate” the dagger, so he can force Drácula and the Wolf Man to turn over their treasure. But while he’s talking to her, the dagger suddenly swivels around in his hand and stabs him! “I’ve committed so many crimes that I’m not human!” Eric gasps and dies. Lina flees, stumbles over the unconscious Santo, and revives him.
Down in the cavern, one of the werewolves is forced to walk a plank across a pit of stakes; naturally, he falls in and is impaled. Now it’s Blue Demon’s turn, only he will have his hands tied behind his back, and Rufus is going to shake the plank! Santo appears and a battle begins. Rosita is rescued and Lina leaves with her. Rufus, after fighting for a while in human form, changes into a werewolf, and his furry sidekicks also join in. Drácula and the Wolf Man team up on Santo, but Blue Demon tosses his pal a rope; Santo swings and knocks the two monsters into the pit, where they are stuck full of holes. The other monsters all turn into little piles of smoky dust.
Santo and Blue Demon find Lina reading “Little Red Riding Hood” to Rosita, who has fallen asleep. Lina: “What will we tell her when she wakes up?” Santo: “That it was all a dream…a nightmare.”
The film ends with a tag team match between Santo and Blue Demon against Renato el Hippie and Angel Blanco.