Significance The transcription factor p53 plays a critical role in the cellular response to DNA damage and has thus been studied intensively in oncogenesis research. However, the role that p53 plays in the response of postmitotic neurons to cellular stress has received less attention. Here we describe an unexpected neuroprotective role for p53 in an in vivo model of tau-mediated neurodegeneration relevant to Alzheimer's disease and related disorders. Further, we identify synaptic function as a novel target pathway for p53 in aging neurons, consistent with the growing evidence for synaptic pathology as an early event in neurodegenerative disease. Our study defines mechanistically a new, conserved role for p53 in protecting postmitotic neurons from degeneration during aging and disease.