Scientist James Bowen and his colleagues Sueko Togami and Kawachi are studying the effects of radiation on survivors from the Hiroshima bombing. During his studies, Doctor Bowen stumbles across a small boy roaming the streets of Hiroshima. Bowen begins to study the child and is amazed when he discovers that the boy is, in fact, Frankenstein's monster, regrown from a dissected heart that was then mutated by the fallout of the atomic bomb. However, the small child quickly grows in size, as it begins to prey on the livestock in the area as a means of food. Upon learning of the creature, and his rapid growth, the Japanese Self Defense Force becomes worried if the beast might turn on a more abundant source of food: humans.

The SDF, after locating Godzilla still trapped in ice in the Bering Sea, decides that freeing the nuclear menace and luring him to Japan to fight off the Frankenstein monster might be their last hope if their fear is realized. Taking action, the military breaks the icy prison from around the creature and lures Godzilla to the Japanese coast with ships. Once there, a series of towers on the mainland lead the King of the Monsters to the Mt. Fuji area. At Fuji, the nuclear menace spots Sueko, but before any harm can come to her Frankenstein rushes to the woman's rescue and does battle with Godzilla. The two titans war is interrupted, though, by a series of volcanic fissures, as one swallows Frankenstein while another causes a great flood which washes Godzilla away in a nearby river.

After Toho's first attempt to produce their own Frankenstein film, Frankenstein vs. the Human Vapour, was scrapped, the company quickly began to adapt other screenplays that incorporated the character. This process led them to pitting the man-made monster up against their most popular creation: Godzilla.

The new screenplay called for a Frankenstein mutated by radiation, causing it to grow to a size to match Godzilla's. However, the screenplay is noteworthy for being the first to pit Godzilla as the lesser of two evils... or at least in the SDF's eyes, as the military would come to rely on the nuclear behemoth to tackle Frankenstein. A resolution in itself which seems odd, as the SDF was going to awaken a creature that has already killed thousands, with no sign of reluctance, to combat a monster which they believe might be dangerous.

The first draft of the project was done by Shinichi Sekizawa, prepped as Godzilla's revival film, but when Universal began to offer Willis O'Brien's King Kong vs. Frankenstein to company, Sekizawa was quickly reassigned. Toho then began work on their most successful science fiction film to date: King Kong vs. Godzilla (1962). Frankenstein vs. Godzilla, now with writer Takeshi Kimura finishing the screenplay, was then moved to a 1964 release as the first draft was finished on July 3rd, 1964. This explains why Godzilla was still encased in ice at the start of the screenplay, as he was at the end of the 1955 Godzilla movie, Godzilla Raids Again (1955). Eventually, though, Frankenstein vs. Godzilla was dropped altogether as Godzilla went off to face Mothra and Ghidorah that same year in Mothra vs. Godzilla (1964) and Ghidorah, the Three-Headed Monster (1964). However, Toho would finally find luck, with finical aid from producer Henry G. Saperstein, in their next attempt with the character: Frankenstein vs. Baragon (1965).