David Feiss originally created Cow and Chicken as a story for his daughter, drawing on years of animation experience at Hanna-Barbera dating back to 1978.

The show began as a pilot for the animation showcase series What a Cartoon! in 1995, one of three ideas Feiss submitted to executive producer Larry Huber; its popularity led Hanna-Barbera to greenlight a full series after fans wrote in asking for more.

A single actor, Charlie Adler, voiced all three lead roles: Cow, Chicken, and the Red Guy.

Guest stars who lent their voices to the series included Will Ferrell, Mark Hamill, Jim Belushi, Dom DeLuise, and the show's creator David Feiss himself.

The second season segment 'Buffalo Gals' was banned by Cartoon Network after receiving a single complaint letter from a parent about perceived lesbian innuendo involving the titular biker gang, and it only ever aired once, on June 27, 1998, before being replaced by 'Orthodontic Police' in all future airings and home releases.

The controversy around 'Buffalo Gals' was later revisited on an episode of Rob Paulsen's Talkin' Toons, where creator David Feiss and voice actor Charlie Adler discussed why the segment only aired once.

The Red Guy made a brief cameo appearance in the Jellystone! episode 'Vote Raspberry,' residing in Hell once again, this time voiced by Dana Snyder instead of Charlie Adler.

Taco Bell promoted the series in February 1999 with a licensed kids' meal featuring five Cow and Chicken toys distributed at 4,200 restaurants.