Purpose <p>Saliva is increasingly recognized as a powerful, noninvasive biofluid for the diagnosis and monitoring of oral squamous cell carcinoma (OSCC), serving as a practical alternative to conventional liquid biopsy. Salivary circulatory DNA (ctDNA) detection in OSCC may exceed plasma levels. emphasizing saliva’s susceptibility to local illness. Saliva collection is simple, non-invasive, and inexpensive, allowing for regular monitoring.</p> Methods <p>Current evidence demonstrates its potential through a wide spectrum of salivary biomarkers.</p> Results <p>Identified salivary biomarkers include viral nucleic acids such as human papillomavirus (HPV), host-derived molecules such as proteins and cytokines (IL-6, IL-8, VEGF), regulatory microRNAs (e.g., miR-21, miR-31, miR-184), and extracellular vesicles containing tumor-specific cargo. Moreover, oral microbiome dysbiosis has been linked to malignant transformation and progression, highlighting saliva’s ability to reflect complex tumor–host interactions. Technological progress in multi-omics profiling and artificial intelligence (AI) has enhanced the interpretation of these multidimensional datasets, supporting the design of more robust and individualized biomarker panels. Concurrently, point-of-care technologies, particularly microfluidic chips and biosensor platforms, are driving the development of rapid and portable saliva-based diagnostics.&#xa0;</p> Conclusion <p>The path toward clinical implementation is constrained by several factors: the absence of FDA-approved salivary assays for OSCC, reliance on relatively small and retrospective studies, and the lack of standardized protocols for collection, processing, and analysis. Despite these challenges, salivary diagnostics are advancing as a highly promising adjunct to established modalities such as histopathology and radiologic imaging. They hold potential in early disease detection, patient stratification, therapeutic monitoring, and surveillance of recurrence. Integrative models, such as liquid TNM staging—which combine salivary and blood-based biomarkers—may ultimately redefine cancer diagnostics and follow-up. To date, no saliva-based assay has received FDA approval for oral cancer, highlighting regulatory and validation shortcomings. For translation into practice, further validation through large-scale trials, regulatory endorsement, and demonstration of cost-effectiveness remain essential. Nonetheless, saliva-based assays stand out as accessible, patient-centered tools with significant implications for the future of head and neck oncology.</p>