Psychological stress impairs adult hippocampal neurogenesis (AHN) and contributes to cognitive dysfunction. Previously, we reported that chronic psychological stress or the stress hormone corticosterone (CORT) induces autophagic cell death (ACD) in adult hippocampal neural stem cells (ahNSCs). However, the regulatory mechanisms underlying this process remain largely unknown. The tumor suppressor gene p53 (Trp53) is abundantly expressed in ahNSCs, yet its function under stress conditions has not been fully elucidated. Here, we demonstrate that, contrary to its well-established pro-apoptotic role, p53 acts as a survival factor that protect ahNSCs from stress-induced ACD. Conditional deletion of p53 in neural stem cells heightened vulnerability to chronic restraint stress (CRS), resulting in worsened memory deficits and mood disturbances compared to wild-type controls. Mechanistically, CORT facilitated LC3-mediated autophagic degradation of p53 through its LC3-interacting region (LIR), thereby promoting ACD. However, overexpression of either wild-type p53 or a degradation-resistant LIR-mutant suppressed ACD by interfering with the ATG14L-containing VPS34 complex. Moreover, treatment with RITA, a small-molecule activator of p53, disrupted the p53-LC3 interaction, stabilized p53 levels, and protected ahNSCs from ACD—ultimately preventing CRS-induced cognitive impairment in the hippocampus. These findings identify p53 as a key negative regulator of ACD in ahNSCs and suggest that p53-stabilizing small molecules could represent a novel class of antidepressant therapies by preserving AHN.