Creator David Feiss came up with I Am Weasel because Cartoon Network demanded a second cartoon to pair with Cow and Chicken in its half-hour time slot.

The show's title and concept originated from a doodle Feiss drew of a weasel captioned 'I Am Weasel', a play on Richard Matheson's novel I Am Legend, one of his favorite books as a teenager; he decided to make the weasel smart and heroic instead of weaselly.

The rivalry between I.M. Weasel and I.R. Baboon was inspired by the classic nursery rhyme 'Pop Goes the Weasel', in which a monkey chases a weasel.

David Feiss originally considered James Earl Jones for the voice of I.M. Weasel because Jones was the announcer for CNN, Cartoon Network's sister channel, but Michael Dorn was ultimately cast after being recommended by Johnny Bravo creator Van Partible.

The Red Guy's lack of pants was reportedly a controversial design choice within the production, but Feiss said Cartoon Network let it go and the Red Guy became his favorite character.

The episode 'I.R. Mommy' had to be digitally censored in 1999, removing the letter 'N' from a football helmet worn by I.R. Baboon, after the University of Nebraska sued Cartoon Network alleging the reference to the Nebraska Cornhuskers was derogatory.

The theme song, a humorous take on 'Pop Goes the Weasel', was composed by Bill Fulton, written by Richard Pursel, and sung by April March.

The season five premiere on June 10, 1999 drew 1.8 million viewers, and the show was the fifth most-watched program on Cartoon Network in 2000, trailing The Powerpuff Girls, Tom and Jerry, Courage the Cowardly Dog, and Dexter's Laboratory.