During the lengthy shooting in Page, Arizona, Dan Aykroyd entertained the local folk by carding guests at a bar, unofficially greeting people at Wal-Mart, and visiting locals for a cup of coffee in their homes.

Initially written as a serious science-fiction thriller, Ivan Reitman hired David Diamond and David Weissman to re-write the project as a comedy. The original writer, Don Jakoby, actually enjoyed the changes so much, he continued working on the film alongside the other writers.

David Duchovny turned down a role in Star Wars: Episode II - Attack of the Clones (2002) to appear in this movie.

Shot in December, DreamWorks asked the locals to delay putting up their Christmas decorations. Following the shoot, DreamWorks paid the city employees overtime to light up the town in time for Christmas.

The placement of the element selenium in Head and Shoulders shampoo is technically correct. Though regular Head and Shoulders shampoo does not have any of the element, Head and Shoulders Intensive Treatment Shampoo actually does consist of approximately 1% selenium sulfide.

The clumsiness in Julianne Moore's character was her idea.

The three main characters perform a commercial for "Head and Shoulders". The idea to this came from Jason Reitman, the son of Ivan Reitman.

Film debut of Ty Burrell.

The reference to selenium is also made in Ivan Reitman's Ghostbusters (1984) as Ray explains the specifics of Dana's building.

Wayne's call of "Ah Ah Ee Ee Tookie Tookie" to the flying monster in the mall was the call of the Tookie Tookie Bird in the cartoon George of the Jungle.

Ted Levine plays Buffalo Bill in The Silence of the Lambs (1991) and Julianne Moore plays Clarice Starling in Hannibal (2001).

In certain point Orlando Jones's character tells David Duchovny to call the government, but he answers "No government, I know those guys". This is a reference to his character in The X Files.

Kevin Dunn appeared as a doctor in an unused alternate ending where it was revealed that Dr. Block had been impregnated by the alien "dragonfly."

Early in the film, the character Nadine says she wants to be Miss Arizona. As the Governor of Arizona is presenting awards to the heroes at the end, Nadine can be seen in the background wearing a "Miss Arizona" sash.