A fishing boat, drifting through Japan's waters, is attacked by a Giant Octopus. The attack is interrupted by another giant who quickly dispatches the mammoth octopus. The other monster, called Gaira, then proceeds to devour the ship's crew, as only one survivor manages to swim to safety. The lone fisherman, now hospitalized, tells his story: of a Frankenstein-like monster that attacked the ship. The authorities begin to assume that this creature has some relation to the one which appeared a year ago, while similar attacks begin to occur near Japan's waterfronts.

Eventually, one such raid leads the beast inland, where the Self Defense Force unleashes a giant assault against the creature. The attack is nearly successful, until a second, larger, monster emerges. This creature, called Sanda, saves the smaller Gaira and leads him to safety. It's then theorized that Gaira was born from the same cells of Sanda, in a similar fashion that the creature was bore from the cells of Frankenstein.

However, the creatures' genetic origin doesn't stop them from eventually battling one another, after the gentler Sanda learns of his "brother's" taste for human flesh. The two monsters' epic battle eventually leads them to Tokyo, where, against advice that continued attacks could severe more cells that would grow into other Frankensteins, the SDF assaults the pair. The confrontation eventually leads out to Tokyo Bay, where helicopters armed with bombs continue to shower the waters near the two. Unfortunately, the bombs activate a giant underwater volcano, which quickly engulfs the monsters as it continues to emerge above the surf. Eventually, the volcano expands into Tokyo Bay, decimating the city in a torrent of lava as the last of the Frankenstein cells are destroyed with it.

First proposed in 1965 by writer Takeshi Kimura, Frankenstein's Sons would eventually go on to become The War of the Gargantuas (1966) after a number of revisions. The first draft was submitted on January 26th, 1966, which changed the title to The Frankenstein Brothers while Ishiro Honda also took on some of the writing. A second draft was then done, which again changed the title, this time to Clash of the Frankensteins. More changes were made, as a third draft was commissioned, which again changed the title as the project now became The Duel of the Frankensteins. A title that almost stuck, although a last minute change, which was literally written onto the already finished script, gave the film it's final title: Frankenstein's Monsters: Sanda vs. Gaira.

In terms of content, early drafts of the script included a lot more references to Frankenstein vs. Baragon (1965) than would end up in the finished product, with some even utilizing the same characters for the sequel. Most of these elements didn't make it far into the development process, though, as The War of the Gargantuas ends up being fairly detached from the events that occurred in the previous film. One major change to note, though, was the very different closure to the movie that earlier drafts had. It was director Honda's original intent that the SDF's second assault, against scientific advice, would be met with dire consequences as the lava then seals the fate of future Frankenstein monsters. This more elaborate ending was dropped by producer Tomoyuki Tanaka, though, citing that it would be too expensive to lens such a sequence, even though Honda suggested that stock footage from the climax of the 1961 film, The Last War, be utilized for the destruction of Tokyo.