Background: Oral Submucous Fibrosis (OSMF) is a chronic, progressive condition characterized by the fibrosis of the oral mucosa, often associated with the habitual consumption of areca nut and tobacco, leading to significant morbidity. Despite its prevalent occurrence in many parts of the world, the underlying genetic and molecular mechanisms remain poorly understood, highlighting a critical need for research into its molecular genomics. The aim of this literature review is to investigate the molecular genomics of Oral Submucous Fibrosis by analyzing the relevant literature of the past decade. Methods: The search was conducted using MEDLINE (National Library of Medicine)-PubMed, focusing on the period 2015–2025 using the following keywords: Molecular Genomics AND Oral Submucous Fibrosis. This was followed by a manual search, and references were used to identify relevant articles. Results: A total of 12 articles were included in our review according to our inclusion criteria, which illustrated the importance of TGF-β, Wnt inhibitory factor-1, CypA, Hsp-70 1B, Calreticulin, Lumican, Enolase 1, MMP-2, IGF-1R, XIST, Epigallocatechin-3-gallate, Von Hippel-Lindau, and MUC1 and 4. Conclusions: Understanding the molecular pathogenesis of OSMF involves examining the molecular interactions and the roles of specific proteins. Advanced genomic technologies have opened new frontiers in the study of OSMF. As research in OSMF continues to evolve, emerging interdisciplinary approaches may provide therapeutic strategies, aiming to improve management outcomes for the patients.