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Oral cancer is one of the most leading cancer responsible for significant morbidity and mortality. The sirtuins (SIRTs) are a family of class III histone deacetylases and are known to regulate a variety of molecular signaling associated with different cancer types including oral malignancies. SIRT1 acts as bifunctional in a variety of cancer. In oral cancer, SIRT1 seems to work as a tumor suppressor. The carcinogenic potential of SIRT1 is also reported in oral cancer, and hence, its role is still ambiguous. SIRT2 is also said to play a dual-faced role in different types of cancers. However, in oral cancer, SIRT2 is not studied and its role remains obscure. SIRT3 expression was positively correlated with oral malignancies. However, studies also showed the anti-cancer role of SIRT3 in oral cancer. SIRT7 loss was observed in oral cancer cells, while its overexpression caused the suppression of oral cancer cells proliferation, migration, and invasiveness. The role of other SIRTs in oral cancer was studied meagerly or reports not available. To date, only the roles of SIRT1, SIRT3, and SIRT7 have been reported in oral malignancies. Therefore, understanding the regulatory mechanisms employed by sirtuins to modulate oral cancer is important for developing potential anti-cancer therapeutic strategies., (© 2021 Wiley Periodicals LLC.)