Oral cancer is a prevalent type of cancer in Asian countries. Several studies indicated that garlic extracts such as diallyl disulfide (DADS) and diallyl trisulfide (DATS) have anticancer effects. However, the inhibitory effects of water soluble garlic extracts, S-allylcysteine (SAC), on the malignant progression of oral cancer have not been studied well yet. Thus, the purpose of this study was to investigate the inhibitory effects of SAC on the proliferation and progression of human oral squamous cancer CAL-27 cells. In the present study, we demonstrated that SAC dose dependently inhibited the growth of human oral squamous cancer cells. Our results showed that SAC induced the expression of E-cadherin adhesion molecule. Immunocytochemical staining result also revealed that SAC could restore the distribution of E-cadherin molecule on cell membrane. We further demonstrated that SAC stabilized the adherent junction complex of E-cadherin/beta-catenin in oral cancer cells. Treatment with the MAPK/MEK specific inhibitor, PD098059, could up-regulate the expression of E-cadherin molecule. Furthermore, SAC significantly inhibited the activation of MAPK/ERK signaling pathway. These findings were associated with the down-regulation of the SLUG repressor protein. In conclusion, our results indicated that SAC effectively inhibited the proliferation, up-regulated the expression of E-cadherin molecule and stabilized the E-cadherin/beta-catenin adherent junction complex in human oral squamous cancer cells. The mechanism of action was in part through the suppression of MAPK/ERK signaling pathway and down-regulation of the SLUG repressor protein.