Purpose: Oral squamous cell carcinoma (OSCC) is one of the most common malignant diseases worldwide, yet its molecular mechanisms are largely unknown. We aimed to construct gene co-expression networks to identify key modules and hub genes involved in the pathogenesis of OSCC. Patients and methods: We used dataset GSE30784 to construct co-expression networks by weighted gene co-expression network analysis (WGCNA). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed by Database for Annotation, Visualization and Integrated Discovery (DAVID). Hub genes were screened and validated by other datasets. Results: Turquoise and brown modules were found to be the most significantly related to tumorigenesis. Functional enrichment analysis showed that the turquoise module was associated with cell–cell adhesion, extracellular matrix and collagen catabolic process. A total of 10 hub genes (MMP1, TNFRSF12A, PLAU, FSCN1, PDPN, KRT78, EVPL, GGT6, SMIM5 and CYSRT1) were identified and validated at transcriptional and translational levels. Their genetic alteration and survival analysis were also revealed. Conclusion: We identified two modules and 10 hub genes, which were associated with the tumorigenesis of OSCC. The two modules provided references that will advance the understanding of mechanisms of tumorigenesis in OSCC. Moreover, the hub genes may serve as biomarkers and therapeutic targets for precise diagnosis and treatment of OSCC in the future.