Multidrug resistance (MDR) remains one of the most significant obstacles in various cancer treatment, and this process often involves dysregulation of the number of micro-RNAs. The aim of this study was to explore the role of miR-4708 on the regulation of MDR-1 expression and the regulation of multidrug resistance (MDR) to chemotherapeutic drugs. Luciferase reporter assays demonstrated that miR-4708 directly binds MDR-1 3’-UTR and down-regulated reporter luciferase activity. The mRNA and protein expression levels of MDR1 were significantly decreased following miR-4708 overexpression. Additionally, the accumulation of rhodamine-123 in paclitacel resistant FaDu cells following miR-4708 transfection was significantly increased compared with control, indicating that the efflux capacity was reduced. These results demonstrated that miR-4708 could be involved in the regulation of MDR via targeting MDR-1 and may provide a potential strategy for reversing drug resistance in oral cancer.