In this study, we provide strong evidence that USP33 directly targets and stabilises p53 tumour suppressor under DNA damage stress condition, and presents anti‐tumour effect supported by the findings that USP33 regulates p53‐dependent DNA damage responses including cell‐cycle arrest and apoptotic induction, and loss of its expression not only promotes HCC cell proliferation and tumorigenicity in nude mice but also accelerates hepatocarcinogenesis induced by DEN in conditional hepatocytic USP33 KO mice. This evidence concerns the gene USP33 and hepatocellular carcinoma.