The Forkhead box M1 transcription factor (FoxM1) is essential for DNA replication and mitosis, and has important role in cell proliferation and apoptosis. To assess the role of FoxM1 in chemoresistance, we investigated FoxM1 protein expression and the correlation between FoxM1 expression, sensitivity to cisplatin-based therapy, and the survival of non-small cell lung cancer (NSCLC) patients. We generated a cisplatin-resistant lung cancer cell line (A549/CDDP) that showed elevated expression levels of FoxM1 protein and mRNA relative to those of the parental A549 cells. We investigated the effect of the knockdown or overexpression of FoxM1 on the sensitivity to cisplatin and the possible signaling transduction pathways in these cells. Our results revealed that the positive expression rate of FoxM1 in NSCLC was associated with chemosensitivity to cisplatin and a poor prognosis. When the expression of FoxM1 was inhibited by RNA interference, the sensitivity to cisplatin was enhanced. Inversely, in FoxM1-overexpressing cell models, we observed a reduced sensitivity to cisplatin. Moreover, we showed that the downregulation of FoxM1 enhanced cisplatin-induced A549/CDDP cell apoptosis through the activation of the c-Jun NH2-terminal kinase (JNK)/mitochondrial pathway. These results suggest that FoxM1 plays a critical role in chemoresistance to cisplatin and that FoxM1 depletion may be a promising approach to lung cancer therapy.