Recent advances in delineating the biological functions of p53 had shed the light on its key role in the multifacets of cellular homeostasis. After its activation, via DNA damage, oxidative stress, or aberrant expression of oncogenes, p53 transduces its classical effect through several mechanisms comprising activation of the DNA repair machinery, cell cycle arrest, and initiation of apoptosis or senescence. In the mammalian brain, p53 plays critical functions in normal development, tumor suppression, neurodegenerative diseases, and aging. Herein, we focus on the constitutive pro-oxidant activity of p53 in neurons and discuss the potential implication of this finding in the context of neurodegenerative diseases and normal brain aging.