In this study, bioinformatic analysis of gene expression data of head and neck squamous cell carcinoma (HNSCC) was performed to identify critical genes. Gene expression data of HNSCC were downloaded from the Cancer Genome Atlas (TCGA) and differentially expressed genes were determined through significance analysis of microarrays. Protein-protein interaction networks were constructed and used to identify hub genes. Functional enrichment analysis was performed with DAVID. Relevant microRNAs, transcription factors, and small molecule drugs were predicted by the Fisher exact test. Survival analysis was performed with the Kaplan-Meier plot from a package for survival analysis in R. In the five groups of HNSCC patients, a total of 5946 DEGs were identified in group 1, 4575 DEGs in group 2, 5580 DEGs in group 3, 8017 DEGs in group 4, and 5469 DEGs in group 5. DEGs in the cell cycle and immune response were significantly over-represented. Five PPI networks were constructed from which hub genes were acquired, such as minichromosome maintenance complex component 7 (MCM7), MCM2, decorin (DCN), retinoblastoma 1 (RB1), and tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein gamma (YWHAG). No significant difference in survival was observed among the 5 groups; however, a significant difference existed between two combined groups (groups 1, 3, and 5 vs groups 2 and 4). Our study revealed critical genes in HNSCC, which could supplement the knowledge about the pathogenesis of HNSCC and provide clues for future therapy development.