Protein 53 (p53) plays a vital role in the human body, mainly as tumor suppressor protein, by inhibiting tumor cell formation and DNA damage through gene target regulation. Known as "guardian of genome", p53 protects genome integrity and prevents cells' proliferation with damaged DNA. In oral squamous cell carcinoma, there is approximately 85% mutation of p53, which leads to impairment of its normal function and often correlated with OSCC progression. Those findings signify the role of p53 in guarding against OSCC, which are through cell cycle arrest, DNA repair, and apoptosis.