Orobanche and Phelipanche species (the broomrapes) are root parasitic plants, some of which cause heavy yield losses on important crops. The development of herbicides based on natural metabolites from microbial and plant origin, targeting early stages on parasitic plant development, might contribute to the reduction of broomrape seed bank in agricultural soils. Therefore, the effect of metabolites belonging to different classes of natural compounds on broomrape seed germination and radicle development was assayed in vitro. Among the metabolites tested, epi-sphaeropsidone, cyclopaldic acid, and those belonging to the sesquiterpene class induced broomrape germination in a species-specific manner. epi-Epoformin, sphaeropsidin A, and cytochalasans inhibited germination of GR24-treated broomrape seeds. The growth of broomrape radicle was strongly inhibited by sphaeropsidin A and compounds belonging to cyclohexene epoxide and cytochalasan classes. Broomrape radicles treated with epi-sphaeropsidone developed a layer of papillae while radicles treated with cytochalasans or with sphaeropsidin A turned necrotic. These findings allow new lead natural herbicides for the management of parasitic weeds to be identified.