The sirtuins (SIRTs) are a family of highly conserved histone deacetylases (HDACs) consisting of seven members (SIRT1-SIRT7). Over the past few decades, SIRT1 has been the most extensively studied and garnered tremendous attention in the scientific community due to its emerging role in cancer biology. However, its biological role in the regulation of oral cancer is not yet fully understood. Owing to contradictory findings regarding the role of SIRT1 in oral cancer, debate about it continues. The present study discusses the biological roles and potential therapeutic implications of SIRT1 in precancerous oral lesions and oral cancer.