Iris nertschinskia, an ornamental plant, is utilized in traditional East Asian medicine for the treatment of skin diseases. However, the biological activity underlying its therapeutic effects remains to be established. In this study, we investigated the anti-tumor effect of the plant extract on MCF7 human breast cancer cells. An ethanol extract of Iris nertschinskia triggered cell death in a dose-dependent manner. Moreover, treatment with the extract promoted p53 phosphorylation in MCF7 cells. Increased phosphorylation of p53, in turn, led to induction of Bax protein, a key regulator of p53-dependent apoptotic cell death, as well as of caspase-7 cleavage in MCF7 cells. Consistently, cells treated with p53-specific siRNA or the caspase inhibitor, Z-VAD, resisted apoptotic cell death induced by the Iris nertschinskia extract. Our results suggest that p53 sensitizes tumor cells to the ethanol extract of Iris nertschinskia by Bax protein induction and caspase-dependent apoptosis.