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The p53 transcription factor coordinates wide-ranging responses to stress that contribute to its function as a tumour suppressor. The responses to p53 induction are complex and range from mediating the elimination of stressed or damaged cells to promoting survival and repair. These activities of p53 can modulate tumour development but may also play a role in pathological responses to stress such as tissue damage and repair. Using a p53 reporter mouse, we have previously detected strong induction of p53 activity in the liver of mice treated with the hepatotoxin carbon tetrachloride (CCl4). Here, we show that p53 functions to support repair and recovery from CCl4-mediated liver damage, control reactive oxygen species (ROS) and limit the development of hepatocellular carcinoma (HCC), in part through the activation of a detoxification cytochrome P450, CYP2A5 (CYP2A6 in humans). Our work demonstrates an important role for p53-mediated redox control in facilitating the hepatic regenerative response after damage and identifies CYP2A5/CYP2A6 as a mediator of this pathway with potential prognostic utility in human HCC.