The sympathetic nervous system (SNS), as an important component of the peripheral nervous system, has emerged as a crucial regulator of solid tumors, from carcinogenesis to progression, metastasis, and pain. This review brings together emerging evidence that SNS signaling is involved in head and neck squamous cell carcinoma (HNSCC) progression, metastasis, and cancer-associated pain. Possible cellular and molecular mechanisms regarding the involvement are also discussed. A systematic literature search was conducted in the PubMed database focusing on SNS, HNSCC, and pain. We found that HNSCC tissues exhibit increased sympathetic nerve innervation compared to healthy tissues. SNS activity modulates key tumor biological processes, including growth and metastasis, angiogenesis, epithelial-mesenchymal transition (EMT), immune responses and apoptosis resistance, through peripheral release of neurotransmitters (primarily noradrenaline) by sympathetic postganglionic neurons or systemic release of epinephrine (Epi) into the circulation by the adrenal medulla. Notably, SNS hyperactivity exacerbates cancer pain via neuro-immune crosstalk, inducing TNF-α, NGF, and BDNF release to sensitize nociceptors. Preclinical studies demonstrate β-blockers suppress HNSCC growth, synergize with chemotherapy/radiotherapy. Therefore, understanding SNS effects on HNSCC biology can offer novel therapeutic targets for this malignancy.