Introduction: Oral submucous fibrosis (OSMF) is a chronic, potentially malignant disorder linked predominantly to areca nut chewing. This study investigates the role of serum trace elements (Cu, Fe, Zn, Se) in the progression and malignant transformation of OSMF. Methodology: A community-based cross-sectional study involved 80 participants from the Government Dental College, Vijayawada, Krishna District, AP. Participants were divided into four groups: areca nut users without OSMF, areca nut users with OSMF, areca nut users with malignant-transformed OSMF, and healthy controls. Blood samples were analyzed for serum iron, copper, zinc, and selenium levels. Results: Significant differences were found in serum copper (P=0.032) and zinc levels (P=0.006), with elevated levels observed in the malignant-transformed OSMF group compared to controls. No significant differences were observed in serum iron (P=0.542) and selenium levels (P=0.062) across the groups. Conclusion: Elevated serum copper levels can serve as a reliable diagnostic marker for malignant transformation in OSMF. Future research should explore the potential therapeutic benefits of copper chelation in OSMF management.