Cutaneous squamous cell carcinoma (cSCC), the second most common form of human cancer, is an epithelial skin tumor, which can result in metastasis with lethal consequences accounting for about 20% of all skin cancer-related deaths. The metastasis is the main reason for cSCC-related deaths with an overall 5-year survival rate < 30% in cases that spread systemically. The role of miRNAs has been involved in SCC of different origins. Recent data have revealed that the expression of miRNA-199a was changed in many human cancers. In this study, we found that miR-199a was significantly decreased in cSCC tissues, which had an inverse relationship with CD44. MiR-199a specifically regulated the expression of CD44 at mRNA and protein levels, and the interaction between CD44 and Ezrin in cSCC cells. Moreover, the suppressive role of miR-199a in cell migration in cSCC cells was also associated with the activity of MMP2 and MMP9. Taken together, our data indicated that increased expression of endogenous mature miR-199a might prevent the growth and migration of human cSCC via decreasing the expression of CD44 and regulating the interaction between CD44 and Ezrin, which may provide a potentially important therapeutic target for human cSCC.