Riluzole is approved by the FDA as an amyotrophic lateral sclerosis (ALS) drug. Previous studies showed that treatment with riluzole suppressed the proliferation of many cancer cells. However, little is known about its effects on nasopharyngeal carcinoma (NPC) and its molecular mode of action. In this study, we determined the effect of riluzole on apoptosis, cell cycle, migration, and invasion in NPC cell lines and investigated its mechanism at the molecular level. By using the human NPC cell lines CNE1, CNE2, and HNE1, we revealed that riluzole effectively inhibited viability of the NPC cell lines in dose- and time-dependent manners. Furthermore, riluzole dose-dependently induced apoptosis and G2/M cell cycle arrest in the NPC cell lines. After combination with radiotherapy (RT), greater cytotoxicity was achieved than with riluzole or RT alone in vitro and vivo. This was associated with the activation of ataxia telangiectasia mutated (ATM) and phosphoinositide p53 pathways. P53 silencing reduced cell reactiveness to riluzole therapy. These observations demonstrate that the riluzole-activated ATM/P53 pathway is directly involved in radiation-induced apoptosis of NPC cells. Given the acceptable side effect, combining of riluzole and radiotherapy is promising in NPC treatment.