Background: Here, we probed the action mechanism of ubiquitin-specific processing proteases 17 (DUB3) in the evolution of oral squamous cell carcinoma (OSCC). Methods: The expression of genes were calculated by qRT-PCR, and proteins were assessed by Western blot and immunohistochemistry. The cells viability and proliferation were checked by MTT and EdU assay, respectively. Flow cytometry was implemented to detect the cell cycle and apoptosis. The activity of EZH2 gene promoter was measured by luciferase reporter assay. Co-immunoprecipitation assay was used to ensure the ubiquitination of bromodomain-containing protein 4 (BRD4). The cell apoptosis of tumor tissues was assessed by TUNEL assay. Results: DUB3 was overexpressed in OSCC tissues and cell lines, and negatively correlated with patient's survival time. DUB3 downregulation could effectively curb OSCC cells viability and proliferation, promote cell apoptosis and the expression of cleaved-caspase-3, cleaved PARP and p21, while inhibit cyclin D1. Besides, DUB3 production was positivity correlated with enhancer of zeste homolog-2 (EZH2) and BRD4. BRD4 downregulation could repress DUB3-induced EZH2 production, and MG132 reversed DUB3 decreasingmediated BRD4 downregulation. Downregulation of DUB3 promoted BRD4 ubiquitination. DUB3 promoted OSCC cells proliferation, while suppressing apoptosis via facilitating EZH2 production. At last, in vivo experiment indicated that the downregulation of DUB3 significantly inhibited the growth of xenograft tumor. Conclusion: In summary, we found that DUB3 enhanced OSCC cells proliferation and xenograft tumor growth, while inhibited their apoptosis via promoting BRD4-mediated upregulation of EZH2. Our study indicated that DUB3 may be an effective anti-cancer target for OSCC therapy.