Background: Tongue squamous cell carcinoma (TSCC) is one of the most common malignant tumors in head and neck, but its molecular mechanism is not clear. Methods: Weighted gene co-expression network analysis (WGCNA) combining with gene differential expression analysis, survival analysis to screen key modules and hub genes related to the progress of TSCC. Gene Set Enrichment Analysis (GSEA) was used to identify biological pathways that might be involved. Results: Weighted gene co-expression network was constructed based on dataset GSE34105. The blue module and turquoise module most related to the progress of TSCC were identified by the network. Gene Ontology (GO) enrichment analysis showed that 2 key modules were significantly enriched in apoptosis and immunity related biological processes and pathway. Network topology analysis, gene difference analysis and survival analysis were used to screen 9 hub genes (NOC2L, AIMP2, ANXA2, DIABLO, H2AFZ, MANBAL, PRDX6, SNX14, TIMM23). The expression of hub genes was significantly correlated with the prognosis of TSCC. GSEA showed that the high expression group of hub genes was mainly enriched in olfactory transduction, neuroactive ligand receptor interaction, nicotinate and nicotinamide metabolism, and the low expression group was mainly enriched in base excision repair, cysteine and methionine metabolism, oxidative phosphorylation. Conclusion: Two key modules and 9 hub genes screened by WGCNA were closely related to the occurrence and prognosis of TSCC. Hub genes can be used as biomarkers and potential therapeutic targets for the accurate diagnosis and treatment of TSCC in the future.