DNA damage repair is a key factor in the maintenance of cell genome stability, plays an important role in the regulation of tumour evolution, and can affect the prognosis of cancer patients. This study aimed to detect the protein expression of the DNA damage repair protein P53 and its upstream and downstream regulators, CHK1, GADD45A, and MDM2, in oral squamous cell carcinoma (OSCC), in order to analyse the association between the expression of these proteins and overall survival, and to assess their prognostic implications for OSCC patients. The expression of the above proteins was detected by immunohistochemistry in 80 human OSCC tissue samples and in non‐cancerous tissue samples. Compared to that in the non‐cancerous tissue, the expression of CHK1, GADD45A, and MDM2 in OSCC tissue was significantly increased. The protein expression of the tumour suppressor gene P53 was also increased. Patients with high CHK1 and MDM2 expression levels had a reduced survival time and a poor prognosis, whereas patients with high GADD45A expression levels had a good prognosis. Our results indicate that high CHK1 expression is an independent risk factor for poor OSCC prognosis, and that CHK1 may be a potential target for OSCC clinical treatment.