Abstract Background: This review evaluates salivary biomarkers—including proteins, cytokines, microRNAs, DNA, RNA, metabolites, and extracellular vesicles—and their diagnostic potential in detecting diabetes, cardiovascular disease, inflammatory bowel disease, autoimmune and neurodegenerative disorders, periodontal disease, oral cancer, and dental caries. Thirty-two peer-reviewed studies (2015–2025) were synthesized to assess saliva’s role as a diagnostic fluid. Methods: A structured search across major databases identified 822 studies. After screening 120 full texts, 34 studies met inclusion criteria (English language, peer-reviewed, diagnostic focus, and biomarker evaluation). Keywords included salivary diagnostics, oral disease biomarkers, systemic disease detection, salivaomics and point-of-care testing. Studies were categorized by disease type, biomarker class, analytical method (ELISA, RT-PCR, microfluidics, biosensors, spectroscopy, AI-based tools), and design. Results: Over 80% of included papers were reviews or meta-analyses emphasizing emerging technologies such as biosensors, microfluidics, and AI-enabled diagnostics. Oral cancer and potentially malignant disorders were most studied, with biomarkers like IL-8, IL-6, CD44, Cyfra21-1, and salivary micro RNAs demonstrating strong diagnostic accuracy. Periodontal studies identified cytokines, proteolytic enzymes, and microbial profiles as reliable indicators of inflammation. Salivary biomarkers such as glucose, cortisol, CRP, calprotectin, alpha-synuclein, and oxidative stress markers showed strong associations with systemic diseases, supporting saliva’s noninvasive diagnostic value. Conclusion: Collective evidence supports saliva as a cost-effective, rapid, and patient-friendly diagnostic fluid for early disease detection and monitoring. Standardized collection protocols, large-scale validation, and advanced technologies will be essential for its integration into precision medicine and clinical practice.