Oral submucous fibrosis (OSMF) is a chronic, progressive, and potentially malignant disorder strongly associated with areca nut use. Characterized by inflammation, fibrosis, and restricted oral opening, OSMF poses significant functional and oncologic challenges. Despite various pharmacological and surgical interventions, no definitive cure exists, and prevention of malignant transformation remains elusive. This review explores the rationale and potential of drug repurposing for OSMF management, highlighting existing medications with novel therapeutic applications and targeting key pathophysiological mechanisms. Literature from 2012 to 2024 was systematically examined, focusing on randomized controlled trials, clinical studies, and mechanistic research involving repurposed drugs for OSMF. Conventional therapies—corticosteroids, enzymes, vasodilators, antioxidants, and physiotherapy—offer symptomatic relief but fail to reverse fibrosis or significantly alter malignant potential. Drug repurposing leverages known safety profiles and shared molecular pathways with other fibrotic diseases, expediting clinical translation. Promising agents include pirfenidone, pentoxifylline, colchicine, metformin, losartan, tamoxifen, interferon-γ, and N-acetylcysteine, which target fibrosis reversal, inflammation modulation, angiogenesis enhancement, and oxidative stress reduction. Mechanism-based approaches focus on TGF-β inhibition, collagen turnover modulation, vascular improvement, and reactive oxygen species scavenging. Drug repurposing offers a cost-effective, time-efficient strategy to expand OSMF treatment options. Future research must prioritize large multicentric trials, dose optimization, and molecularly guided personalized medicine to develop effective, accessible, and sustainable therapies. By bridging mechanistic insights with clinical application, repurposed agents hold promise for improved functional outcomes and reduced malignant transformation risk in OSMF.