ObjectiveTo screen the differentially expressed genes (DEGs) of head and neck squamous cell carcinoma (HNSCC) and to further explore their underlying molecular mechanisms.MethodsThe HNSCC Gene Chip Datasets, downloaded from the Gene Expression Omnibus (GEO) database, were identified by GEO2R and analyzed by gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) pathway. The proteinprotein interaction (PPI) networks of these DEGs were constructed using Cytoscape software. Furthermore, UALCAN database was use to perform survival analysis.ResultsA total of 143 DEGs were screened out. Of them, 50 were upregulated and 93 downregulated. The DEGs were significantly enriched in GO terms of collagen catabolic process, cell adhesion and proteolysis. The pathways were enriched in drug metabolism, NFκB signaling pathway, ECM?receptor interaction, complement and coagulation cascades. Thus 15 hub genes related to HNSCC were obtained by PPI analysis. Among them, PLAU, SPP1 and TIMP1 were identified as clinically relevant genes.ConclusionSPP1 is a good target for cancer therapy and a marker for guiding radiotherapy. PLAU and TIMP1 may be key genes and potential therapeutic target genes for HNSCC. PLAU and SPP1 may regulate the development of HNSCC through the NFκB signaling pathway and IL17 signaling pathway.