Background: Oral premalignant lesions (OPLs) are precursors to oral cancer, a significant global health issue. Sulindac, a non-steroidal anti-inflammatory drug (NSAID), has shown promise in the chemoprevention of various cancers. This retrospective study evaluates the efficacy of Sulindac in reducing the progression of OPLs in a cohort of patients from Darbhanga, Bihar. Materials and Methods: A retrospective study was conducted over one year; involving 30 patients were diagnosed as OPLs. Patients were treated with Sulindac 150 mg twice daily for six months, followed by a six-month observation period. Clinical evaluations and histopathological assessments were performed at baseline, 3 months, 6 months, and 12 months. The primary endpoint was the regression of OPLs, determined by clinical and histopathological criteria. Results: Out of the 30 patients, 25 completed the study. At the end of 12 months, 60% (15/25) of the patients showed partial regression of OPLs, while 20% (5/25) exhibited complete regression. No significant change was observed in 20% (5/25) of the patients. Histopathological analysis revealed a reduction in dysplasia grade in 50% (10/20) of the patients who had initial moderate to severe dysplasia. Adverse effects were mild, with gastrointestinal disturbances being the most common. Conclusion: Sulindac demonstrates potential efficacy in the chemoprevention of oral premalignant lesions, with a significant proportion of patients showing regression of lesions and reduction in dysplasia grade. Further prospective studies with larger sample sizes are warranted to confirm these findings and establish optimal dosing regimens.