TP53 is the most frequently mutated gene in cancer, yet these mutations remain therapeutically non-actionable. Major challenges in drugging p53 mutations include heterogeneous mechanisms of inactivation and the absence of broadly applicable allosteric sites. Here we report the identification of small molecules, including arsenic trioxide (ATO), an established agent in treating acute promyelocytic leukemia, as cysteine-reactive compounds that rescue structural p53 mutations. Crystal structures of arsenic-bound p53 mutants reveal a cryptic allosteric site involving three arsenic-coordinating cysteines within the DNA-binding domain, distal to the zinc-binding site. Arsenic binding stabilizes the DNA-binding loop-sheet-helix motif alongside the overall β-sandwich fold, endowing p53 mutants with thermostability and transcriptional activity. In cellular and mouse xenograft models, ATO reactivates mutant p53 for tumor suppression. Investigation of the 25 most frequent p53 mutations informs patient stratification for clinical exploration. Our results provide a mechanistic basis for repurposing ATO to target p53 mutations for widely applicable yet personalized cancer therapies. Display omitted •ATO rescues multiple p53 mutants effectively in various assays•The structural mechanism of how mutant p53 function is restored by ATO is described•Most p53 mutants are stabilized structurally but only some are transcriptionally rescued•Widely applicable, yet has individual p53 mutation-based therapeutic potential Chen et al. show that ATO, an FDA-approved drug, robustly rescues mutant p53, uncover the underlying molecular mechanism, and report the rescue pattern among frequent p53 mutants.