Our previous studies had revealed that the dysregulation of manganese superoxide dismutase (SOD2) expression was a frequent event in tongue squamous cell carcinoma (TSCC) and may be associated with enhanced metastatic potential. To further evaluate the mechanism of SOD2-mediated metastasis in TSCC, TSCC cell lines with different metastatic potential (i.e., the highly metastatic UM1 line and the UM2 line, which displays fewer metastases) were used. Compared to UM2 cells, UM1 cells exhibited significantly higher SOD2 activity and intracellular H2O2, higher protein levels of Snail, MMP-1 and pERK1/2, lower protein levels of E-cadtherin, and not difference of catalase activity. Upon knockdown of SOD2 by RNA interference, UM1 cells displayed significantly reduced migration and invasion abilities, reduced activities of SOD2, lower intracellular H2O2, decreased protein levels of Snail, MMP-1 and pERK1/2, and increased protein levels of E-cadtherin. Migration and invasion ability of UM2 and SOD2 shRNA-transfected UM1 cells were enhanced by H2O2 treatment and accompanied by increased protein levels of Snail, MMP-1 and pERK1/2, and decreased protein levels of E-cadtherin. Moreover the migration and invasion ability of UM1 cells were decreased after catalase treatment. Thus, we conclude that the SOD2-dependent production of H2O2 contributes to both the migration and invasion of TSCC via the Snail signaling pathway through increased Snail, MMP-1 and pERK1/2 protein levels, and the repression of the E-cadtherin protein.