Objective To investigate the expression of calcium-activated neutral protease Calpain-2 in oral squamous cell carcinoma (OSCC) and the effect of Calpain 2 on tumor cells. Methods The expression of Calpain-2 in OSCC tissues was detected by RT-PCR, Western blotting and immunohistochemistry, and the relationship between Calpain-2 and clinicopathology was analyzed. OSCC cells without Calpain-2 were used to evaluate the effects of Calpain-2 on cell proliferation, apoptosis and migration. Results The expression of Calpain-2 was increased in OSCC clinical samples (P?0.05). There was no significant difference in proliferation and apoptotic rate of OSCC cells without Calpain-2 compared with the control group (P?>?0.05). Knocking down the expression of Calpain-2 significantly inhibited the migration of OSCC cells (P?0.05). Conclusions Calpain-2 may be involved in the migration of cancer cells and may become an important target for inhibiting the migration of cancer cells.