Effective therapeutic strategies to target mut-p53 cancer cells remain an urgent and unmet medical need. We have found that mut-p53 impairs the function of the transcription factor, NRF2, to regulate genes involved in cellular detoxification in response to oxidative stress. We show that mut-p53 accumulation across represses the transcription of NRF2 target genes, including SLC7A11, a key component of the glutamate/cystine exchanger, system xCT-. Downgregulation of SLC7A11 by accumulation of mut-p53 results in reduced cystine import, lowering endogenous stores of the major cellular anti-oxidant, glutathione. This in turn raises basal reactive oxygen species (ROS) levels and predisposes cells to oxidative damage. Notably, genetic or pharmacological inhibition of system xCT- creates a synthetic lethal interaction with mut-p53 accumulation, a therapeutic paradigm similar to the use of PARP inhibitors in BRCA deficient cancers. Moreover, we found that APR-246, a first-in-class reactivator of mut-p53, depletes cellular glutathione and induces significantly higher amounts of ROS in mut-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. APR-246 also reverses the suppressive effect of mut-p53 on NRF2 and SLC7A11 expression, a potential negative feedback mechanism that antagonises drug activity. In extension, we demonstrate that antagonising system xCT- activity in combination with APR-246 selectively and synergistically inhibits mut-p53 cancer cells. Together, our findings propose that accumulation of mut-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 NRF2/xCT-/glutathione axis.