BACKGROUND: Oral Submucous Fibrosis (OSMF) is a chronic, progressive condition linked to areca nut consumption, with a high potential for malignant transformation into oral squamous cell carcinoma (OSCC). Changes in lipid metabolism have been implicated in cancer biology, yet the relationship between lipid profiles and OSMF progression remains underexplored. This study investigates the alterations in serum lipid parameters across different clinical stages of OSMF and their association with malignant transformation. MATERIALS AND METHODS: A cross-sectional study was conducted over 69 OSMF patients, divided into five groups (Stage 1 to 3 and Stage 4a, 4b) based on clinical staging. Serum lipid profiles, including total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL), very low-density lipoprotein (VLDL), and triglycerides (TG), were analyzed. Statistical analysis was performed using ANOVA and Tukey's post hoc test. RESULTS: Lipid levels (TC, HDL, LDL, VLDL, TG) showed a significant decline from Stage 1 to Stage 4a (p-0.00), followed by a sharp increase in Stage 4b (p-0.00), coinciding with malignant transformation. Particularly, HDL, VLDL, and TG were significantly elevated in Stage 4b compared to earlier stages. CONCLUSION: Alterations in lipid metabolism (hypolipidemia) were observed from Stage 1 to 4a, with a marked shift (hyperlipidemia) during malignant transformation (Stage 4b). Increased levels of HDL, VLDL, and TG in advanced OSMF stages suggest their potential as predictive biomarkers for malignancy. Further research is required to elucidate the mechanisms linking lipid metabolism with OSMF progression and malignancy, paving the way for targeted therapeutic strategies.