Oral squamous cell carcinoma (OSCC) is the most prevalent type of malignant epithelial neoplasm that affects the oral cavity. It has been a significant health concern in many countries for a long time since it was usually treated with surgery, radiation, and/or chemotherapy. Drug resistance is the primary issue in patient populations and scientific research, which promotes OSCC tumour cell invasion and migration. Thus, identifying highly specific therapeutic targets could be the potential approach for more successful treatment of OSCC. It is still challenging to understand the genetic causes of oral carcinogenesis due to its highly varied clinic-pathological parameters. It is important to remember that signaling channels and complexes that affect chromatin accessibility control gene expression, which in turn affects cell development and differentiation. Histones undergo post-translational alteration to give this platform. Understanding the processes of gene regulation through histone methylation and its modifications could enhance the early detection, prognostic prediction, and therapy of OSCC. To be properly used as a therapeutic target, histone methylation in OSCC requires more investigation. This review details the dysregulated histone methylation and the modifying enzymes linked to the development and aetiology of OSCC. Furthermore, the part that lysine methylation plays in cell migration, chemo-resistance, and OSCC invasion is also investigated.