OBJECTIVE: This review presents an overview of the current knowledge on smokeless tobacco and oral cancer, with a specific focus on South and Southeast Asia. METHOD: The recent literature on the association of smokeless tobacco and oral cancer, its biological mechanisms, and policies for prevention and control, was reviewed. In addition, its role in the causation of oral cancer and allied diseases was assessed its biological mechanisms resulting in deleterious health outcomes and steps to control its use. RESULTS: Of the more than 360 million people who consume smokeless tobacco globally, nearly 80% reside in the region. The evidence of an association between the numerous SLT products consumed in the region and oral cancer is well established, with oral snuff and gutkha showing the strongest association. More than 4000 chemical ingredients are present in these products, many of which are involved in the intricate biological pathways leading to carcinogenesis. CONCLUSION: Given the deep cultural integration of SLT products, effective control measures require multifaceted approaches that combine education, regulation, and community engagement. Collaborative efforts among governments, healthcare professionals, and communities are essential to address this urgent issue and mitigate the substantial human and economic costs.