Salvia divinorum was first recorded in print by Jean Basset Johnston in 1939 as he was studying the psilocybin mushroom use of the Mazatecs in Mexico. R. Gordon Wasson later documented its usage and reported its effects through personal testimonials. Additional historical references are lacking. It was not until the 1990s that this plant's properties became widely known through the experiment and report of Daniel Siebert.

It is likely that Salvia divinorum has a longstanding relationship with humans. Wasson theorized that this plant was the mythological pipilzintzintli, the "Noble Prince" of the Aztec codices. However, this theory is not without dispute. The Aztecs were extremely knowledgeable in plant identification, and their records report that pipilzintzintli has both male and female varieties. Salvia divinorum, however, is monoecious, meaning it produces flowers of both sexes on a single plant. Skeptics of this theory report that the Aztecs would have known the difference between male and female flowers. Wasson gains validity, however, as a number of Aztec historical accounts engender plants in a metaphorical, rather than botanically anatomical manner.