Natural products drug discovery has allowed the identification of many biologically active compounds from plants, microbial species, and marine organisms. A significant number of these compounds are currently used as drugs in therapeutic protocols, while other naturally occurring chemical entities gave suggestions for designing nonnatural-product derived drugs or have been modified in their structure to have semi-synthetic analogues. In the last decade, experimental evidence that correlated the aberrant activation of the Hedgehog (Hh) signaling pathway with many types of cancer, prompted the researchers to check natural compounds for their ability to modulate this signaling cascade. As a result, many compounds from natural sources showed inhibitory activity toward one or more of the Hh signaling pathway components, such as Smoothened (Smo) and the downstream effectors Gli. On the other hand, only a few natural compounds were able to stimulate the same pathway. This review reports a survey of the compounds extracted from natural sources (especially plants) that showed activity in inhibiting the Hh signaling machinery by interfering with its components.