Oral squamous cell carcinoma (OSCC) is a common malignancy worldwide. This study clarified the oncogenic role of miR-134 in OSCC. Reporter assays, using both wild-type and mutant constructs, confirmed that Programmed Cell Death 7 (PDCD7) gene was a potential target of miR-134. The OSCC cells exogenously expressed miR-134 exhibited reduced PDCD7 expression. As expected, exogenous miRZip-134 expression increased PDCD7 expression in the OSCC cells; additionally, PDCD7 expression suppressed the oncogenicity of the OSCC cells. By contrast, PDCD7 knockout through gene editing increased in vitro oncogenicity and neck nodal metastasis in nude mice, and reduced E-cadherin (E-cad) expression. PDCD7 transactivated E-cad expression via the GC-box in the promoter. Moreover, miR-134-associated cellular transformation and E-cad downregulation was attenuated by PDCD7. Downregulation of both PDCD7 and E-cad and high levels miR-134 expression was observed in OSCC tumor tissues. Activation of the miR-134-PDCD7-E-cad pathogenesis cascade occurred early during the human and murine oral carcinogenesis process. In conclusion, the oncogenic effect of miR-134 in oral carcinoma is mediated by reducing PDCD7 and E-cad expression. This article is protected by copyright. All rights reserved.