Saliva plays a multifaceted role in oral health and systemic well-being. It supports digestion, protects oral tissues, maintains a healthy oral microbiome, and facilitates wound healing. Additionally, saliva serves as a diagnostic tool that reflects systemic health and disease/therapeutic states. Furthermore, although saliva shows a protective effect against oral cancer development, once tumor formation occurs, it may be involved in tumor progression and metastasis via exosomes and microRNAs. This review discusses the essential role of saliva; its relationship with the development, progression, and metastasis of head and neck squamous cell carcinoma (HNSCC); liquid biopsy tools for early diagnosis and monitoring of HNSCC; and the potential of exosomes as therapeutic agents.