Aim: To identify and validate salivary microRNA (miRNA) signatures as non-invasive biomarkers for predicting malignant transformation in oral potentially malignant disorders (OPMD), specifically oral submucous fibrosis (OSMF) and leukoplakia (OL). Methodology: A cross-sectional, STROBE-compliant study included OSMF, OL, oral squamous cell carcinoma (OSCC), and healthy controls. Unstimulated saliva was collected via passive drooling. miRNA isolation was optimized using a column-based method (Qiagen RNeasy Advanced Plasma/Serum Kit), and nucleic acid quality was assessed using QIAxpert. Discovery profiling was performed using the NanoString nCounter platform (>700 miRNAs). Twenty samples passing quality control (Normal n=3, OSMF n=8, OL n=3, OSCC n=6) were analyzed. Data were normalized and assessed using ROSALIND with Student’s t-test (p<0.05). Digital PCR validation is ongoing. Results: Optimized isolation improved RNA yield and enabled robust profiling. All 20 samples met QC criteria. Distinct miRNA signatures were identified in OSMF and OL, with enrichment of malignant transformation pathways. In OSMF, shared miRNAs (miR-758-5p, miR-202-3p, miR-381-3p, miR-455-3p, miR-432-5p) were linked to IGF1R and MAPK8 regulation, promoting fibrosis, extracellular matrix deposition, and inflammation. Interaction with CDKN1A and MDM2 indicated disruption of p53-mediated control. In OL, miRNAs (miR-582-3p, miR-103a-3p, miR-590-3p, miR-450b-3p) targeted CCND1 and KRAS, suggesting dysregulated G1/S transition and MAPK/PI3K activation. In OSCC, convergence of these pathways showed upregulation of CCND1, KRAS, and IGF1R with MDM2 overexpression and CDKN1A alteration, reflecting enhanced proliferation and apoptosis evasion. A progressive miRNA–gene network from fibrosis (OSMF) to oncogenic activation (OSCC) was observed. Conclusion: Salivary miRNA profiling shows strong potential as a non-invasive biomarker for early detection and risk stratification in OPMD.