Oral squamous cell carcinoma (OSCC) remains the main cause of cancer mortality, accounts for 90% of oral cancers. Increasing evidence reveals that aberrant expression of microRNA contributes to the development and progression of OSCC, but the roles of microRNA-506 (miR-506) in OSCC remain elusive. Here, we found that the expression of miR-506 was decreased in 21 OSCC tissues and SCC-4 and SCC-9 cells. miR-506 overexpression suppressed proliferation, migration and invasion capabilities of OSCC cells. Moreover, miR-506 overexpression suppressed the luciferase activity of the GATA6-Wt 3'-UTR and decreased the mRNA and protein levels of GATA6. GATA6 overexpression attenuated the suppressive effects of miR-506. Furthermore, GATA6 was increased in OSCC tissues compared with the adjacent normal tissues and inversely associated with miR-506. Taken together, these results suggest that miR-506 is an important suppressor and could be a novel prognostic factor and therapeutic target for OSCC patients.