Currently, the main approach to nasopharyngeal carcinoma (NPC) treatment is radiotherapy (RT), but for many NPC patients, RT is not effective. Increasing RT sensitivity of NPC cells would provide a significant treatment advance for NPC patients. While γ-secretase inhibitors (GSIs) have gained recent attention as novel anticancer drugs, the mechanism of action of GSIs as radiosensitizers is not well understood. In the present study, radiation-induced anti-proliferative effects of the one GSI (N-[(3,5-difluorophenyl)acetyl]-L-alanyl-2-phenyl]glycine-1,1-dimethylethyl ester, DAPT), on CNE2 cells were investigated with the MTT assay; in vitro radiosensitization effects were evaluated by the apoptosis assay and the cell colony formation assay. The activation status of the Notch signaling pathway in DAPT- or dimethyl sulfoxide-treated CNE2 cells was also examined. Notch signaling in NPC cells was found to be down-regulated by DAPT; therefore, DAPT could significantly inhibit CNE2 growth and improve NPC radiosensitization, thus, enhancing RT-induced anti-proliferative effects and apoptosis. Taken together, our data show that Notch signaling down-regulation by GSIs could enhance radiosensitivity of NPC cells, suggesting clinical applications for GSIs as radiosensitizers for NPC therapy.