Oral squamous cell carcinoma (OSCC) is a multistep process which is modulated by several endogenous and environmental factors. Epigenetic changes have been found to be equally responsible for OSCC as genetic changes. A plethora of genes showing hypermethylation have been discovered in OSCC. Since these changes are reversible, a lot of emphasis is on using the natural compounds for their ability to cause demethylation which could lead to reactivation of the inactivated tumor suppressor genes. This review encompasses the promoter hypermethylation of tumor suppressor genes in OSCC and its possible reversal using natural compounds. In addition, new compounds which could be screened for their demethylating ability have also been proposed.