Oral cancer has become a significant problem throughout the world, particularly in countries that are still developing. Recent literature supports the contribution of components of the tumor microenvironment (TME) and the effect of epigenetic changes happening in the cells of the TME on oral cancer development and progression. In this review, we comprehensively examine the significance of TME in the development of OC along with the current understanding of the epigenetic modifications that regulate the TME and their cohesive impact on tumor traits and their potential as therapeutic targets.