Vascular endothelial growth factor C (VEGF-C) has been reported to be responsible for the lymphatic vessel density, tumor staging and lymph node metastasis, resulting in the failure of nasopharyngeal carcinoma (NPC) after radiotherapy. Therefore, the aim of this study was to explore the effects and the underlying mechanism of VEGF-C on the radiotherapy and in the human NPC cell lines CNE-2. In our study, VEGF-C silenced CNE-2 cells were stably established. Different small interfering VEGF-C (si-VEGFC) were transfected into CNE-2 cells and combined with 8 Gy X-ray. The proliferation, cloning ability, DNA damage, and apoptosis of CNE-2 cells were evaluated by counting kit-8 (CCK-8), colony-forming assay, comet assays, and flow cytometry, respectively. Moreover, the VEGFC knockdown involved signaling pathways in CNE-2 cells were predicted by polymerase chain reaction (PCR) array, and validated by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Western blot analysis. Results demonstrated that silencing VEGF-C combined with radiation can significantly inhibit the proliferation and cloning ability, while increase the apoptosis and DNA damage of CNE-2 cells, thereby promote the radiosensitivity. Furthermore, the effects of silencing VEGF-C probably through activating the NF-kappa B signal pathway. In conclusion, the study demonstrated that VEGF-C may be a potential target to increase the radiosensitivity in NPC by activating NF-kappa B signaling.