The tumour suppressor gene p53 is required to maintain the integrity of the genome, and mutations in the TP53 gene are one of the more common types of genetic alterations in oral cancer. Collectively, the above studies have presented many genes and pathways affected by TP53 mutations in oral squamous cell carcinoma (OSCC). First, we will present the physiological functions of wild-type p53 and the types of TP53 mutations in oral cancer. Then we will discuss how the mutant TP53 promotes cancer by both loss-of-function (LOF) and gain-of-function (GOF) mechanisms in cell cycle regulation, apoptosis, DNA damage repair and metabolism. We will also study whether TP53 mutation status is associated with other characteristics of the clinicopathological features of the tumour, treatment response and patient prognosis. Emerging therapeutic strategies of the p53 pathway include mutant p53 reactivation, synthetic lethality and inhibition of downstream signalling pathways. Finally, I will briefly list the present problems and future directions of P53-based strategies for precision medicine in oral cancer.