Nasopharyngeal carcinoma (NPC), the most common cancer in head and neck regions, is a serious health problem worldwide. Neuropilin and tolloid-like 2 (NETO2), a member of the subfamily of CUB domain and LDLa-containing proteins, has been suggested to be involved in tumor progression. Nevertheless, little is known about the function and molecular mechanism of NETO2 in NPC progression. In the study, NETO2 was found to be significantly up-regulated in clinical tissues and NPC cell lines. NETO2 expression was positively correlated with tumor size. NETO2 knockdown inhibited cell proliferation, migration and invasion in NPC cell lines. Significantly, NETO2 knockdown promoted the radiotherapy in vitro, as evidenced by the further reduced cell proliferation and metastasis in NPC cells using 3-[4, 5-dimethylthiazol-2-yl]-2, 5 diphenyl tetrazolium bromide (MTT), colony formation and transwell analysis. In addition, NETO2 inhibition markedly induced apoptosis in NPC cells through activating Caspase-3 signaling. Also, the knockdown of NETO2 obviously promoted the efficacy of radiotherapy in apoptosis induction, along with higher expression of cleaved Caspase-3. NETO2 knockdown-triggered apoptosis in NPC cells were considerably diminished by Caspase-3 inactivation, demonstrating the essential role of Caspase-3 in NETO2-regulated NPC development. Moreover, in vivo experiments suggested that NETO2 knockdown promoted radiation-induced tumor growth suppression in the absence of significant side effects. Collectively, reducing NETO2 expression might elevate the efficiency of radiotherapy in NPC patients.