Radiotherapy and adjuvant cisplatin chemotherapy are the mainstream approaches in the treatment of nasopharyngeal carcinoma (NPC). These have been shown to effectively improve the outcome and reduce tumor recurrence. However, radiotherapy and chemotherapy resistance during the course of treatment has become more common recently, resulting in the failure of NPC therapy. Therefore, new therapeutic strategies or adjuvant drugs are urgently needed. The current study was designed to look for new treatment strategies or auxiliary drugs in the treatment of NPC. Two human NPC cell lines, HNE1 and HNE1/DDP, were used to examine the relationship between endoplasmic reticulum stress and cell resistance to ionizing radiation (IR) and cisplatin (DDP). Cell proliferation was assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Meanwhile, propidium iodide (PI) staining and PI/Annexin V staining were used to observe cell apoptosis. Finally, western blot was used to detect the endogenous expression of glucose-regulated protein 78 (GRP78) and other apoptosis-related proteins. GRP78 small interference RNA was transfected using Lipofectamine 2000. Compared with HNE1/DDP, IR and DDP increased the cell apoptosis and inhibited the cell proliferation of HNE1. Inhibition of GRP78 can reverse IR and DDP resistance in NPC cells by PI/Annexin V staining. Knockdown of GRP78 upregulates the expression of pro-apoptotic proteins and downregulates the expression of antiapoptotic proteins. These results indicate that HNE1 is more sensitive to DDP and IR than HNE1/DDP. Knockdown GRP78 can reverse IR and DDP resistance in NPC cells. Inhibition of GRP78 gives us a new target to overcome resistance to radiotherapy and chemotherapy of NPC cells. Thus, this study should be further explored in vivo and assessed for possible clinical applications.