A close friend of fellow comedians Terrance and Phillip, O'Brien was an early viewer and fan of their feature film, Terrance and Phillip: Asses of Fire but he sold them out to Mothers Against Canada, ultimately leading to his famous, televised suicide attempt. He survived and continued to host Late Night With Conan O'Brien, where he introduced the world to Carlos Mencia, the 'true creator' of the Fishsticks joke. He was later put out of work by Funnybot and joined his rival Jay Leno and friend Adam Sandler in confronting the students of South Park Elementary.
- South Park: Bigger, Longer & Uncut
- Do the Handicapped Go to Hell? (s04e10; cameo)
- Fishsticks (s13e05)
- Funnybot (s15e02; cameo)
- During the 2005 Emmy Awards, yet another version of O'Brien (voiced by himself) appeared in Stan Marsh's closet, rehashing the infamous scene from "Trapped in the Closet".
- In "Do The Handicapped Go to Hell?" he appears in Hell, deceased after film, but he is alive again almost a decade later without explanation in "Fishsticks".
- Conan O'Brien has had at least three voice actors in South Park-related media: Brent Spiner in the film, himself in the Emmy Awards short, and an unknown actor (most likely Matt Stone) in "Fishsticks".