Cryptotanshinone, a natural compound isolated from the roots of Salvia miltiorrhiza Bge (Danshen), has been found to induce cancer cells apoptosis and impair cell migration and invasion in various malignancies, but its antiproliferation and chemosensitization effects of Cryptotanshinone on tongue squamous cell carcinoma(TSCC)still remain fully elucidated. In this study, the effects of Cryptotanshinone on the proliferation, apoptosis and cell cycle of human TSCC cells, including CAL 27 and SCC 9 cells, were measured. The results demonstrated that Cryptotanshinone dose-dependently inhibited cell migration and proliferation, and induced apoptosis in TSCC cells. Mechanistic study revealed that Cryptotanshinone suppressed the expression of p-STAT3, Bcl-2, CDK2, Snail and MMP2, and induced the expression of E-cadherin, P53, P21 and β-catenin. Furthermore, we found that the combination treatment of Cryptotanshinone and paclitaxel more effectively inhibited TSCC cell proliferation and migration, and induced apoptosis via the inhibition of STAT3 signaling pathway. In brief, we provided the new evidence that Cryptotanshinone could enhance the efficacy of paclitaxel on TSCC cells in vitro and demonstrated that STAT3 signaling pathway played an important role in Cryptotanshinone-induced anticancer effects in human TSCC.