Growing evidence supports that microRNAs (miRNAs) play crucial roles in cancer progression by directly downregulating multiple targets. However, the underlying mechanisms of miRNAs in oral squamous cell carcinoma (OSCC) are poorly understood. In the current study, we found that miR-194 expression was markedly downregulated in both clinical OSCC tissues and OSCC cell lines, compared with adjacent non-cancerous tissues and normal tongue epithelial cell TEC, respectively. Overexpression of miR-194 suppressed, whereas miR-194-in promoted OSCC cell proliferation. Furthermore, we demonstrated that miR-194 could reduce the phosphoinositide 3-kinase (PI3K)/AKT/FoxO3a signaling pathway by suppressing acylglycerol kinase (AGK) directly, resulting in decreasing cyclin D1 expression and increasing expression of p21 in OSCC. In sum, our data provide compelling evidence that miR-194 functions as a potential tumor suppressor by inhibiting the PI3K/AKT/FoxO3a signaling pathway and might sever as a potential therapeutic target for OSCC patients.