Natural products remain the best sources of drugs and drug leads. Various anticancer drugs are derived from the natural products. In our previous studies, we found that methanol extract of Pterocarpus santalinus exhibited potent cytotoxicity and anti-inflammatory activities. Among the series of compounds isolated from Pterocarpus santalinus, melanoxoin demonstrated the highest cytotoxic effects with a IC50 of 1.98 μg/ml in human non-small cell lung cancer H1299 cells. The results showed that melanoxoin regulated the transcription of several cell cycle regulators in H1299 cells. Melanoxoin induced tubulin depolymerization, suggesting that melanoxoin causes G2/M arrest thus increasing apoptosis in tumor cell. The results of neutral comet assay showed that treatment with melanoxoin induced significant DNA damage in H1299 cells, while the in vivo efficacy of melanoxoin was revealed by the mice xenograft models. Clinical data showed that an increase (61%) of MET expression was observed in non-small cell lung cancer samples compared with adjacent normal tissues.