Heparanase (HPSE), an endo-β-D-glucuronidase, is overexpressed in nasopharyngeal carcinoma (NPC). The purpose of our study was to investigate the possible role of HPSE in the development of NPC. RNA interference (RNAi) using an HPSE small hairpin RNA (HPSE shRNA) was used to identify the effects of HPSE on the regulation of the malignant behaviors of NPC. CNE-2, a highly metastatic human NPC cell line in which HPSE mRNA and protein levels were detected to be the highest in three NPC cell lines involved in the research, was selected as a cell model in vitro and in vivo. The results showed that downregulation of HPSE significantly inhibited the proliferative and invasive abilities of CNE-2 cells partially through MAPK signaling. Compared with the parental NPC cells, HPSE-silenced cells exhibited attenuated capacity for developing tumors in nude mice, while the growth of tumor xenografts derived from these cells was dramatically suppressed. In conclusion, our results suggest that HPSE contributes to the proliferation and metastasis of NPC, and HPSE may be a potent molecular target for NPC treatment.