Gliomas are the leading cause of death among adults with primary brain malignancies. Treatment for malignant gliomas remains limited, and targeted therapies have been incompletely explored. In this study, we found that the protein expression of presenilin 2 (PS2) was significantly increased in glioma tissues, at least partially because of promoter demethylation. We further evaluated the biological functions of PS2 in U251 glioma cell proliferation, migration, invasion, and tumor growth in vivo by specific inhibition of PS2 using short hairpin RNA (shRNA). We found that PS2 depletion inhibited glioma cell growth as the result of inhibited proliferation and induced apoptosis. PS2 depletion also decreased the invasive capability of glioma cells and anchorage-independent colony formation in soft agar. Moreover, suppression of PS2 expression significantly impaired the growth of glioma xenografts in nude mice. Finally, the decrease in glioma cell growth caused by PS2 depletion seems to involve Nrg1/ErbB signaling. In summary, our data highlight the use of RNA interference (RNAi) as a tool to better understand the molecular basis of PS2 in glioma progression and to uncover new targets for the treatment of glioma.