When making the second season, Cartoon Network wanted David Feiss to keep on making "I. M. Weasel" shorts. David Feiss didn't want to make any more, but agreed he would only if he could start using the Red Guy in the "I. M. Weasel" shorts. Since then, the Red Guy was a regular character in Weasel.
The episode "Buffalo Gals" was banned after its first airing, due to sexual references and lesbian stereotypes. The episode involved a pack of biker girls who wore buffalo hats (hence the name) busting into Cow and Chicken's house and tearing up the place. The leader takes a liking to Cow and they kidnap her, which means Chicken must go to her rescue.
The first Cow and Chicken short had rougher animation than the series that followed, and featured much darker themes. In the first cartoon, Chicken goes to Hell for smoking cigarettes, and is tortured by The Devil while he's there. After this harsh episode, the content of the series was toned down, the animation was brightened up, and The Devil's name was changed to "The Red Guy".
It was David Feiss' ex-wife Pilar Menendez's idea to have Cow's alter-ego, Supercow speak only in Spanish.
Charlie Adler based the voices of Cow after Ellen Greene, and Chicken after himself at the age of fourteen.