Purpose Oral cancer has the characteristics of rapid progression, wide invasion and poor prognosis, which induces higher mortality in the patients. At present, there are about 300 thousand new cases of oral cell carcinoma worldwide. Particularly, the incidence rate of oral cancer in China is relatively high. Therefore, it urgently needs to understand the pathogenesis of oral cancer and molecular mechanisms underlying. Abnormal regulation of miR-219-5p is present in various types of cancer. However, the relationship between miR-219-5p and its targets in oral cancer has not been well evaluated. Methods Western blotting and Quantitative RT-PCR were used to detect the expression of SOX5 in oral cancer tissues.Migration ,cell proliferation,and invasion were detected using CCK8 assay,Conlony formation assay and Transwell assays .The interaction between SOX5 and miR-219-5p and oral cancer was confirmed using dual-luciferase reporter assays.Result This study aims to investigate the possible roles of miR-219-5p and its potential target gene, SOX5, in the progress of oral cancer. Our data showed that the high miR-219-5p and low SOX5 expression levels were associated with improved survival rates in patients. miR-219-5p level was negatively correlated with the expression of SOX5. Genetic analysis and luciferase assay revealed that the miR-291-5p regulated SOX5 expression by targeting the 3'-UTR region of SOX5 mRNA. Functionally, we confirmed that miR-219-5p mimics inhibited SOX5 expression and suppressed the proliferation, colony formation ability, invasion and migration of oral cancer cells, SCC4 and SCC9. In contrast, inhibition of miR-219-5p increased SOX5 levels and promoted the vitality and mobility of oral cancer cells. Furthermore, special siRNA targeting SOX5 partially neutralized the effects of miR-219-5p inhibitor. Conclusions This study demonstrates that miR-219-5p may inhibit the proliferation, migration and invasion of oral cancer by targeting the expression of SOX5, which provided novel candidates for clinic prognosis and/or therapy.