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The tumor suppressor protein p53 is essential for neuronal death in several experimental settings and may participate in human neurodegenerative disorders. Based upon recent studies characterizing chemical inhibitors of p53 in preclinical studies in the cancer therapy field, we synthesized the compound pifithrin‐α and evaluated its potential neuroprotective properties in experimental models relevant to the pathogenesis of stroke and neurodegenerative disorders. Pifithrin‐α protected neurons against apoptosis induced by DNA‐damaging agents, amyloid β‐peptide and glutamate. Protection by pifithrin‐α was correlated with decreased p53 DNA‐binding activity, decreased expression of the p53 target gene Bax and suppression of mitochondrial dysfunction and caspase activation. Mice given pifithrin‐α exhibited increased resistance of cortical and striatal neurons to focal ischemic injury and of hippocampal …