Mantle cell lymphoma (MCL) is an aggressive and mostly incurable B-cell malignancy with frequent relapses after an initial response to standard chemotherapy. Therefore, novel therapies are urgently required to improve MCL clinical outcomes. In this study, MCL cell lines were treated with pterostilbene (PTE), a non-toxic natural phenolic compound primarily found in blueberries. The antitumor activity of PTE was examined by using the Cell Counting Kit-8, apoptosis assays, cell cycle analysis, JC-1 mitochondrial membrane potential assay, western blot analysis, and tumor xenograft models. PTE treatment induced a dose-dependent inhibition of cell proliferation, including the induction of cell apoptosis and cell cycle arrest at the G0/G1 phase. Moreover, the PI3K/Akt/mTOR pathway was downregulated after PTE treatment, which might account for the anti-MCL effects of PTE. Synergistic cytotoxicity was also observed, both in MCL cells and in xenograft mouse models, when PTE was administered in combination with bortezomib (BTZ). The antitumor effects of PTE shown in our study provide an innovative option for MCL patients with poor responses to standardized therapy. It is noteworthy that the treatment combining PTE with BTZ warrants clinical investigation, which may offer an alternative and effective MCL treatment in the future.