The critical tumour suppressor, p53, is mutated in over half of all human cancers. Loss of wild-type p53 activity together with oncogenic gain-of-function, secondary to aberrant accumulation of mutant p53 protein, frequently results in aggressive tumour phenotype, resistance to conventional therapies and poor survival. Therefore, effective therapeutic strategies to target mutant p53 cancer cells remain an urgent and unmet medical need. We have found that mutant p53 impairs the function of the transcription factor, NRF2, a master regulator of genes involved in cellular detoxification in response to oxidative stress. We show that mutant p53 accumulation across multiple tumour types represses the transcription of NRF2 target genes, including SLC7A11, a key component of the amino acid transporter, system xCT-. Downgregulation of SLC7A11 by mut-p53 results in reduced cystine import, lowering endogenous glutathione stores, raising basal reactive oxygen species (ROS) levels and predisposing cells to oxidative damage. Notably, genetic knockdown or pharmacological inhibition (erastin and sulfasalazine) of system xCT- preferentially induces apoptosis in cancer cells with mutant p53 accumulation. Moreover, we found that APR-246, a first-in-class reactivator of mutant p53 currently in early clinical trials, depletes cellular glutathione and induces significantly higher amounts of ROS in mutant p53 cancer cells compared with normal cells. This leads to lipid peroxidation of mitochondrial membranes and the release of matrix contents, culminating in apoptotic cell death. APR-246-induced cytotoxicity could be rescued by cysteine or glutathione replacement, or with lipophilic antioxidants. In extension, we demonstrate that antagonising system xCT- activity in combination with APR-246 selectively and synergistically inhibits mutant p53 cancer cells. Together, our findings propose that accumulation of mutant p53 protein in cancer cells, through its repressive effects on SLC7A11 expression, creates an ‘Achilles heel’ that can be targeted by further perturbations of the glutathione pathway.