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Objective: This study postulates that distinct patterns in salivary gene expression clusters among HNSCC patients provide valuable insights into diagnostic and prognostic markers for the disease. The aim is to identify critical genes and their protein-protein interactions through bio-computational analyses, contributing to a deeper understanding of HNSCC progression. Ultimately, the hypothesis anticipates the discovery of novel molecular signatures in saliva, potentially enhancing early detection and prognostic precision in head and neck squamous cell carcinoma. Materials and methods: A comprehensive keyword search was conducted to extract 74 salivary gland secretion genes from the Human Protein Atlas. GeneMANIA and STRING databases were employed to analyse protein-protein interactions and predict functional partners. UALCAN facilitated the visualization of salivary gland secretion gene expression patterns in HNSCC, providing insights into survival analysis. Results: In HNSCC compared to normal tissue, CHRM3, GYLTL1B, MMP3, and WDR91 were identified as statistically upregulated genes, while the downregulated genes included AGFG2, CCDC64B, CD24, CRISP3, CXCL17, ELF5, KRT7, MANSC1, MYO5C, PRR4, SCGB3A1, SH3YL1, TCN1, TRPV6, and ZG16B. Kaplan–Meier survival curve analysis revealed that high expression of salivary genes such as AGFG2, AMY1A, CCDC64B, CCL28, C4ORF7, GYLTL1B, TMEM211, LMX1B, ODAM, SCGB3A1, and SLC26A9 was significantly associated with poorer overall survival outcomes in HNSCC patients. Conclusion: This study identifies distinct salivary gene expression patterns in HNSCC, highlighting potential diagnostic and prognostic markers. Specific upregulated genes, such as CHRM3 and GYLTL1B, and downregulated genes, including AGFG2 and CCDC64B, offer insights into HNSCC progression. Elevated expression of particular genes correlates with poorer overall survival, emphasising their prognostic significance.