The film started as an adaptation of a horror comic book, Rex Havoc, in which a monster hunter Rex and his team of experts called "Ass-Kickers of the Fantastic" fight against ghouls, ghosts and other creatures. The earliest development goes back to 2002, when DreamWorks first filed for a Rex Havoc trademark. In a plot synopsis revealed in 2005, Rex was to assemble a team of monsters, including Ick!, Dr. Cockroach, the 50,000 Pound Woman and Insectosaurus, to fight aliens for disrupting cable TV service. In the following years, the film's story diverged away from the original Rex Havoc, with directors Conrad Vernon and Rob Letterman finally creating the storyline from scratch.
Production designer David James stated that the film is "a return to what made us nerds in the first place," getting classic movie monsters and relaunching them in a contemporary setting. Director Conrad Vernon added that he found it would be a great idea to take hideous monsters and give them personalities and satirize the archetypes. Each of the five monsters has traits traceable to sci-fi/horror B movies from the 1950s, 1960s and 1970s, although none is a mere copy of an older character. Susan, who grows to be 49 feet 11 inches tall into Ginormica, was inspired by Attack of the 50 Foot Woman. Dr. Cockroach represents The Fly and The Curse of Frankenstein, while B.O.B. is an amalgam of slithering and slimy characters that were featured in the films, including The Blob and The Crawling Eye. Insectosaurus, a 350-foot-tall monster, is a nod to the 1961 Kaiju film Mothra. According to Vernon, the Missing Link has no direct inspiration. He "just represents anything prehistoric that comes back to life and terrorizes people." For the San Francisco sequence, the producers researched many films and photographs for an accurate depiction of the city, and filmed animator Line Andersen, who had a similar body type to Ginormica—tall, thin, and athletic-looking—walking alongside a scale model of San Francisco, to capture better how a person not comfortable with being too big with an environment would walk around it.
Ed Leonard, CTO of DreamWorks Animation, says it took approximately 45.6 million computing hours to make Monsters vs. Aliens, more than eight times as many as the original Shrek. Several hundred Hewlett-Packard xw8600 workstations were used, along with a 'render farm' of HP ProLiant blade servers with over 9,000 server processor cores, to process the animation sequence. Animators used 120 terabytes of data to complete the film. They used 6 TB for an explosion scene.
Starting with Monsters vs. Aliens, all feature films released by DreamWorks Animation were produced in a stereoscopic 3D format, using Intel's InTru3D technology. 2D, RealD 3D, IMAX 3D, and 4DX versions were released.