This study aimed to elucidate the antitumor activity of norcantharidin (NCTD) against human mantle cell lymphoma (MCL). Cell proliferation and apoptosis were examined by MTS and flow cytometry. Caspase-3, -8, and -9 activities were detected with a colorimetric caspase protease assay. Apoptotic proteins-including PARP, cyclin D1, Bcl-2 family proteins, XIAP, and cIAP I-were studied by western blot. The phosphoinositide 3 kinase (PI3K) inhibitor LY294002 was used to investigate the involvement of the PI3K/Akt signaling pathway. In vivo studies were performed using Z138 cell xenografts in nude mice. NCTD inhibited proliferation and induced apoptosis of Z138 and Mino cells, both in vitro and in vivo. PI3Kp110 α and p-Akt expressions were downregulated by NCTD treatment. NCTD downregulated NF- κ B activity by preventing NF- κ B phosphorylation and nuclear translocation. This effect was correlated with the suppression of NF- κ B-regulated gene products, such as cyclin D1, BAX, survivin, Bcl-2, XIAP, and cIAP. This phenomenon was blocked by the PI3K inhibitor LY294002. Our results demonstrated that NCTD can induce growth arrest and apoptosis in MCL cells and that the mechanism may involve the PI3K/Akt/NF- κ B signaling pathway. NCTD may have therapeutic and/or adjuvant therapeutic applications in the treatment of MCL.