Evolution was based on a story by Don Jakoby, but director Ivan Reitman had writers David Diamond and David Weissman rewrite much of the script to transform it into a comedy he described as a 'modern-day successor to Ghostbusters.'

The rewrite incorporated elements from another screenplay by Todd Phillips and Scot Armstrong about three friends hunting aliens, and Jakoby was initially upset by the tonal shift before working with the new writers to approve the final product.

The original script ended with a 'battle of wits' between humans and an ultra-intelligent alien species, but this was replaced with the more action-packed climax seen in the final film.

Ivan Reitman had previously worked with David Duchovny on Beethoven (1992) and specifically envisioned him as the lead for Evolution because of his ability to handle comedy.

David Duchovny discussed a role in the Star Wars prequels Attack of the Clones and Revenge of the Sith with George Lucas but turned it down partly due to his schedule filming Evolution, seeking to distance himself from his X-Files image.

Seann William Scott was cast after impressing Reitman with his performance in Road Trip (2000), beating out Jerry Trainor, who instead received a smaller role in the film.

Michael J. Fox was offered a lead role in the film but declined due to his ongoing battle with Parkinson's disease.

Filming took place from October 19, 2000, to February 7, 2001, in Page, Arizona, and around Los Angeles, with college scenes shot at California State University, Fullerton, and mall scenes at Hawthorne Plaza.

The very first scene filmed for the movie was the monster attack on two elderly women.

Tippett Studio designed over 18 distinct alien creatures for the film, each with a unique appearance, while Sony Pictures Imageworks handled CGI for sequences like the flatworm alien and a leech alien designed by Peter Konig.

The score was composed by John Powell and performed by the Hollywood Symphony Orchestra, with the soundtrack album released through Varèse Sarabande rather than DreamWorks Records or Sony Music, despite the film's studio ties.