Tongue squamous cell carcinoma (TSCC) is one of the most common malignant tumor types in the oral and maxillofacial region. The etiology and pathogenesis behind TSCC is complicated. In the present study, three gene expression profiles, namely GSE31056, GSE13601 and GSE78060, were downloaded from the Gene Expression Omnibus (GEO). The GEO2R online tool was utilized to identify differentially expressed genes (DEGs) between TSCC and normal tissue samples. Furthermore, a protein-protein interaction (PPI) network was constructed and hub genes were validated and analyzed. A total of 83 common DEGs were obtained in three datasets, including 48 upregulated and 35 downregulated genes. Pathway enrichment analysis indicated that DEGs were primarily enriched in cell adhesion, extracellular matrix (ECM) organization, and proteolysis. A total of 63 nodes and 218 edges were included in the PPI network. The top 11 candidate hub genes were acquired, namely plasminogen activator urokinase (PLAU), signal transducer and activator of transcription 1, C-X-C motif chemokine ligand 12, matrix metallopeptidase (MMP) 13, secreted phosphoprotein 1 (SPP1), periostin, MMP1, MMP3, fibronectin 1 (FN1), serpin family E member 1 and snail family transcriptional repressor 2. Overall, 83 DEGs and 11 hub genes were screened from TSCC and normal individuals using bioinformatics and microarray technology. These genes may be used as diagnostic and therapeutic biomarkers for TSCC. In addition, SPP1 and FNl were identified as potential biomarkers for the progression of TSCC.