Natural products continue to represent the main source for therapeutics, and ethnopharmacological remedies from high biodiversity regions are a rich source for the development of novel drugs. Hence, in our attempt to find new anti-neoplastic activities we focused on ethno-medicinal plants of the Maya, who live in the world's third richest area in vascular plant species. Pluchea odorata (Asteraceae) is traditionally used for the treatment of various inflammatory disorders and recently, the in vitro anti-cancer activities of different extracts of this plant were described. Here, we present the results of bioassay-guided fractionations of the dichloromethane extract of P. odorata that aimed to enrich the active principles. The separation resulted in fractions which showed the dissociation of two distinct anti-neoplastic mechanisms; firstly, a genotoxic effect that was accompanied by tubulin polymerization, cell cycle arrest, and apoptosis (fraction F2/11), and secondly, an effect that interfered with the orchestrated expression of Cyclin D1, Cdc25A, and Cdc2 and that also led to cell cycle arrest and apoptosis (fraction F3/4). Thus, the elimination of generally toxic properties and beyond that the development of active principles of P. odorata, which disturb cancer cell cycle progression, are of interest for potential future therapeutic concepts against proliferative diseases.