The episode's writer, David X. Cohen, developed the idea after visiting the American Museum of Natural History, and decided to loosely parallel themes from the Scopes Monkey Trial.

Springfield's residents are convinced it is the remains of an angel, and Homer cashes in by moving the skeleton into the family's garage, charging visitors to see it.

[2] He initially wanted Lisa to find a "missing link" skeleton, and do an episode reminiscent of the Scopes Monkey Trial.

[2] Writer George Meyer convinced him instead to have the focus be on an angel skeleton, while keeping an emphasis on the conflict between religion and science.

[4] Dan O'Brien cited the episode in a discussion of ontology, skepticism, and religious faith, in his book An Introduction to the Theory of Knowledge.

[6] Lisa's frustration with the marketing gimmick used by the mall developers is seen by Turner's Planet Simpson: How a Cartoon Masterpiece Documented an Era and Defined a Generation as yet another example of her conflict with corporations throughout the series.

[11] The study group is asked to debate the episode in the context of skepticism as related to other unexplained phenomena, including UFOs, the Loch Ness Monster, the Abominable Snowman, the Bermuda Triangle, Atlantis, near-death experiences, reincarnation, mediumship, psychics, and fortune-telling.

[11] In Pinsky's book itself, he noted that Lisa faced the difficult task of confronting religious hysteria and blind faith, and also attempted to reconcile science within her own belief system.

[12] The publicity stunt created by the mall developers in the episode has been compared to scientific hoaxes such as the Cardiff Giant and the Piltdown Man.

[12] When Lisa asks if the townspeople are outraged at the end of the episode for being fooled by a publicity stunt, Chief Wiggum is about to answer her but is distracted when he catches sight of a Pottery Barn in the new Heavenly Hills mall.

[15] In the July 26, 2007 issue of Nature, the scientific journal's editorial staff listed the episode among "The Top Ten science moments in The Simpsons".

[16] "Lisa the Skeptic" was utilized in a Salt Lake City Episcopal Church Sunday School class in 2003, to stimulate a discussion among fourteen-year-olds about belief in angels, and the juxtaposition of science and faith.

[18] A group of The Simpsons enthusiasts at Calvin College have also analyzed the religious and philosophical aspects of the episode, including the issue of faith versus science.