Head and neck cancers (HNCs) are malignant tumors that differ from carcinomas in their biological behaviour and require a different diagnostic and treatment approach, especially in cancers like lung, breast, and prostate. Exosomal RNA (exRNA), particularly miRNA, mRNA, and lncRNA in blood or other body fluids through liquid biopsy, is emerging as a non-invasive biomarker for early cancer detection, prognosis, and treatment monitoring. Exosomal RNA modulates key signalling pathways like NF-κB, EGFR, PI3K/AKT/mTOR, and TP53 and contributes to the development, progression and therapeutic resistance of cancers. In this review, we focus on the roles of exosomal RNA in the growth and evolution of head and neck squamous cell carcinoma (HNSCC) as well as the emerging therapeutic strategies targeting exosomal RNA to improve clinical outcomes in HNC patients. © 2025 Elsevier B.V., All rights reserved.