Mantle cell lymphoma (MCL) is an aggressive non‑Hodgkin lymphoma (NHL) with poor prognosis. The rapid progression and frequently relapse make it urgent to identify therapeutic agents with potent antitumor effect. Increasing evidence indicated that dysregulation of Wnt/β‑catenin pathway and abnormal methylation appeared to promote tumorigenesis. Arsenic trioxide (As2O3, ATO) has been reported effective in many hematologic malignancies in recent studies, however, the mechanism and effects of ATO in MCL still need further research. In this study, ATO was shown to promote apoptosis and to inhibit cell viability in MCL cell lines, whereas, the expression of DNA methyltransferase-1 (DNMT-1), β‑catenin and the downstream molecules of Wnt/β‑catenin pathway such as c‑myc, cyclin D1 and MMP7 were all decreased in a dose-dependent manner with ATO. ATO also attenuated upregulation of β‑catenin after LiCl stimulation and provided synergistic effect with 5-azacytidine (5-azaC) on the DNMT-1 inhibition. The results indicated that ATO may suppress MCL by targeting Wnt/β‑catenin pathway and DNMT-1. These findings may guide drug usage of ATO in clinical therapy for MCL.