The aim of the present study was to investigate the key genes, miRNAs and pathways in hypopharyngeal squamous cell carcinoma (HPSCC) and to elucidate the mechanisms underlying HPSCC development. The gene and microRNA (miRNA) expression profiles of HPSCC tissues and adjacent normal tissues from three subjects were obtained. Differentially expressed genes (DEGs) and differentially expressed miRNAs were identified in HPSCC. Functional annotation and protein‑protein interaction (PPI) network were conducted to elucidate the biological functions of DEGs. A total of 160 DEGs (16 upregulated and 144 downregulated genes) and 79 differentially expressed miRNAs (48 upregulated and 31 downregulated miRNAs) were identified in HPSCC. The deregulated genes were significantly involved in spliceosome, cell cycle and RNA degradation. In the PPI network, S‑phase kinase associated protein 1 (SKP1), non‑POU domain containing octamer binding (NONO) and zinc activated ion channel (ZACN) were identified as hub proteins. On the whole, the present study may help to gain a comprehensive understanding of tumorigenesis in HPSCC and provide valuable information for early diagnosis and drug design of HPSCC in future research.