One of the enemies in the "Secret of the Oracle" episode, Dopefish, was a "stupid little fish" created by the game's designer Tom Hall and described in-game as "the second-dumbest creature in the universe" (in reference to the dumbest creature in the universe, the Ravenous Bugblatter Beast of Traal from Douglas Adams' "The Hitchhiker's Guide to the Galaxy" franchise). Dopefish has since gone on to develop a cult following by becoming one of the biggest recurring in-jokes in the video game industry due to the sheer amount of games it has made appearances in (a large chunk of which having Tom Hall's involvement).

As of October 2021, Dopefish has made known appearances in Wacky Wheels, Rise of the Triad, Duke Nukem 3D, Shadow Warrior, Quake, Quake II, Quake III Arena, Jazz Jackrabbit 2, SiN, Descent 3, Battlezone, Kingpin, Daikatana, Anachonox, Max Payne, Hyperspace Delivery Boy, Commander Keen (2001), Return to Castle Wolfenstein, Eternal Daughter, Hitman 2: Silent Assassin, Red Faction, Congo Cube, The Frozen Throne expansion to Warcraft III: Reign of Chaos, SiN Episodes: Emergence, Chili Con Carnage, TAGAP: The Apocalyptic Game About Penguins, Fortress Forever, OFF, Dystopia, Alan Wake, Deus Ex: Human Revolution, Pettington Park, Rocketbirds: Hardboiled Chicken, Warsow, Bombshell, Doom (2016), Wolfenstein II: The New Colossus, Ion Fury, and Doom Eternal.

Beyond video games, Dopefish notably made cameo appearances in two animated series: "Tiny Toon Adventures" in the 1992 episode "Toon TV" during the song "Toon In, Toon Out", which aired less than a year after Dopefish's debut, and "Lakewood Plaza Turbo", the pilot episode to the 2017 series "OK K.O.! Let's Be Heroes".

In the Temple of the Moons level in the "Secret of the Oracles" episode, there are moon drawings on the floor. Standing idle on one of these drawings will make Commander Keen moon the player, as opposed to reading a book (his normal idle animation).