Previous cytotoxic (anticancer) evaluations of Elephantopus mollis were mainly focused on its elephantopin derivatives neglecting the combined effect of the phytochemicals in its traditionally used extracts. In this study, the cytotoxic mechanism of its extracts was investigated using methylene blue assay. The cytotoxic screening results revealed the ethyl acetate extract as the most potent extract by displaying prominent dose-dependent and time-dependent growth inhibitions in human liver carcinoma HepG2 cells with the lowest EC₅₀ value of 9.38 ± 0.43 µg/mL after 72 hours of treatment. Acute exposure of the HepG2 cells to the ethyl acetate extract produced a significant regulation of caspase-3 with the peak expression at 8 hours of treatment (P < .05). DNA fragmentation indicated by DeadEnd Apoptosis Detection System–labeled nuclei cells confirmed that the extract induced apoptotic cell death through caspase-3-dependent pathway in HepG2 cells.