Use and management of wild and weedy species may involve artificial selection, which can determine morphological, physiological, reproductive, and genetic divergences between wild and managed populations, resulting in the initial or incipient phases of plant domestication. In this study we combined ethnobotanical, morphological, phytochemical and genetic information for analyzing differences between managed and unmanaged populations of the Mexican edible weed, Epazote (Chenopodium ambrosioides L.), in Santa María Tecomavaca, Oaxaca, a rural community within the Tehuacán-Cuicatlán Biosphere Reserve, Mexico. Our hypothesis was that differences in morphology (e.g. leave dimensions and density of pubescence), phytochemistry (e.g. flavor, odor, and amount of strong scented and toxic compounds) and/or molecular genetic markers, between managed and wild populations of Epazote in Santa María Tecomavaca, would indicate that managed populations have been and/or are under a process of incipient domestication. Our results revealed the existence in the study area of morphological variants associated with a gradient of management intensity, which involved apparent improved palatability correlated with a lowering of chemical defense. Most remarkably, we found agreement in the groupings defined by the cluster analyses of morphological and genetic data. Although Epazote is considered a weed or, at best, a minor crop, the results from four lines of evidence (cultural differentiation patterns, gigantism, reduction in chemical defenses, toxic compounds and inheritance of adaptive traits) suggest the existence of an incipient domestication process in the study zone.