In the NES version of the game, despite heavy censorship, the scene where the player can put a hamster into a microwave oven was left in the game. Nintendo discovered this just as the first run was being shipped to retail, and stipulated that no more copies could be manufactured until that scene was censored.

In later versions of the game, including the PAL version, attempting to put the hamster in the microwave will only cause the game to respond "HOW SICK!"

While working on Maniac Mansion, Ron Gilbert coined the term "cutscene." He used this term to describe a scene that cut away from the action of the game. There was a command in Maniac Mansion's code called "cut-scene" that automatically saved the game and restored it once the scene was over. While other games had scenes that would play between levels or after a boss fight, Maniac Mansion was one of the first games to incorporate scenes in the middle of gameplay.

Only a few weeks after the game went on sale, it was pulled from shelves at Toys R Us due to a complaint over the word "lust" printed on the back of the box, which prompted a revision of the game's packaging.