Two new and six known arylnaphthalene lignan lactones were discovered from Phyllanthus poilanei Beille (Phyllanthaceae) collected in South Vietnam. The structures of the new compounds were determined by interpretation of their spectroscopic data, with the structure of one of these new compounds, phyllanthusmin D, being confirmed by single-crystal X-ray diffraction analysis. Several of these compounds were cytotoxic toward the HT-29 human colon cancer cells, with phyllanthusmin D found to be potently cytotoxic in vitro showing an IC50 value of 170 nM and active when tested in an in vivo hollow fiber assay. This compound showed a different mechanism of action when compared with etoposide. It mediated its cytotoxicity toward the HT-29 cells by induction of tumor cell apoptosis through activation of caspase-3 with no inhibitory activity against DNA topoisomerase IIα.