This film is considered the last entry in the Golden Age of Toho's kaiju films, and meant to be the last film of the Godzilla series. However, it was successful enough that it was decided to continue the series, albeit as part of a film campaign called the Toho Champion Festival, a seasonal matinee that specifically targeted children. This meant that subsequent films would have to reduced their budgets and staff since the Godzilla films were just too expensive to continue making in their original manner. For example, this film and the ones prior had two or more large groups of crew members that divided the work on the character drama and special effects sequences. Case in point: cinematographer Taiichi Kankura shot the live action character drama directed by Ishirô Honda, while different cinematographers, Yôichi Manoda and Motoyoshi Tomioka, shot the monster sequences directed by Sadamasa Arikawa. Subsequent films reduced this to a singular crew that had to manage all of those aspects at once.
Director Ishirô Honda wanted the film to have a greater focus on the inner workings of Monsterland; for example, how the monsters were fed and given water, several underwater scenes, and early concepts of monsters being "created" on the island through biotechnology. However, despite the film having a larger budget, such ideas were deemed too expensive by Toho, leaving the opening segment as the only remnant of Honda's original vision for the film. Budgetary constraints also applied to which monsters were included and ultimately excluded from the film, such as Ebirah from Ebirah, Horror of the Deep (1966), Sanda and Gaira from The War of the Gargantuas (1966) (who were the spawn of Frankenstein (the monster from the earlier film Frankenstein vs. Baragon (1965))), King Kong, and Maguma, the giant walrus from another earlier film, Gorath (1962). Toho's rights to King Kong had reverted back to RKO before filming could begin and Honda personally disliked Maguma.
The Japanese title of this film actually translates as "Monster Total Advancement". The title "Destroy All Monsters" was Toho's international title used for overseas sales. These titles were usually changed when the films were released in the U.S. and Europe; however, this one was kept.
The final film in the Godzilla series to involve all four "founding fathers": Tomoyuki Tanaka (producer), Ishirô Honda (director), Akira Ifukube (score) and Eiji Tsuburaya (special effects, although he only worked as an advisor).
This is only the second film in the Godzilla series up to this point since Godzilla (1954) in which Godzilla himself actually appears in or attacks Tokyo. In Godzilla Raids Again (1955) Godzilla appears in Osaka, in King Kong vs. Godzilla (1963) he never actually makes it to Tokyo, in Mothra vs. Godzilla (1964) he appears in Nagoya, in Ghidorah, the Three-Headed Monster (1964) he appears in Yokohama, in Invasion of Astro-Monster (1965) he is taken from Lake Myojin by the Xiliens and then appears in the Nagano Prefecture, while Ebirah, Horror of the Deep (1966) and Son of Godzilla (1967) both take place on two fictional South Pacific islands.