The title is reminiscent of the 1956 movie The Man Who Knew Too Much starring James Stewart and Doris Day, and more recently, the 1997 movie The Man Who Knew Too Little starring Bill Murray. This is the third time this title has been parodied. The first two being "The Boy Who Knew Too Much" and "The Dad Who Knew Too Little".
The advertising campaign Bart and Lisa watch in the theatre mentioned above is for a restaurant called "The Hillside Wrangler", a parody of Kenneth Bianchi and Angelo Buono who were called the Hillside Stranglers. Part of the Eisenhower Expressway is also called the Hillside Strangler.
When Lisa finds Dr. Nick in the cemetery, he puts four severed arms around his body and says, "I'm not Dr. Nick, I am Dr. Octopus!", a reference to Dr. Octopus, the super-villain of the Spider-Man series. Also, he speaks some lines referencing the series, mentioning Spidey (Spider-Man) and Mary Jane Watson. The comment about the upside down kiss references the 2002 Spiderman movie.
During the Itchy & Scratchy cartoon, Scratchy attends the musical Cats and finds the show so boring that he shoots himself in the head.
Lisa says she learned from Scooby-Doo that the only thing to fear are crooked real estate developers. This is a reference to the show's frequent plotline of the ghosts not being real, but staged by unscrupulous individuals for financial gain; for example, lowering property values in order to buy up real estate at a bargain price and later turn a profit by developing and reselling it.
The song at the beginning is "Eve of Destruction" by Barry McGuire.