Background <p>Non-invasive biomarker-based approaches are urgently needed to support early identification and monitoring of Oral squamous cell carcinoma (OSCC) and its precursor, oral submucous fibrosis (OSMF).</p> Methods <p>We employed combined metabolomic and proteomic analyses to profile saliva and lesion surface swabs from clinically diagnosed OSCC (<i>n</i> = 15), OSMF (<i>n</i> = 20), and healthy controls (<i>n</i> = 27). Polar and nonpolar metabolites were extracted separately from saliva, while proteins were isolated from exfoliated mucosal epithelial cells. Differential expression, pathway enrichment, and biomarker classification were performed across four comparisons: OSCC vs non-OSCC (controls + OSMF), OSCC vs OSMF, OSMF vs control, and OSCC vs control.</p> Results <p>Distinct molecular changes were observed across the health-to-cancer spectrum. Top discriminatory salivary metabolites included linoelaidic acid, gamma-glutamylcysteine, and 3-hydroxybutyryl-CoA, implicating dysregulated linoleic acid metabolism, redox imbalance, and fatty acid β-oxidation in pathogenesis. Proteomic data revealed significant upregulation of histone variants, cytoskeletal keratins, and BPI-fold-containing proteins in OSCC, reflecting chromatin remodelling and epithelial-mesenchymal transition. Multivariate biomarker panels achieved high accuracy (AUC ≥ 0.96) for classifying OSMF from OSCC.</p> Conclusion <p>Our combined metabolomic and proteomic profiling revealed non-invasive molecular signatures for early detection and monitoring of OSCC and OSMF.</p>