Autophagy dysfunction contributes to NLRP1 inflammasome-linked depressive-like behaviors in mice. This study investigated the relationship between autophagy and the NLRP1 inflammasome in depression using a chronic social defeat stress (CSDS) model. The results showed that CSDS exposure caused a bidirectional change in hippocampal autophagy function, with activation in the initial period and impairment at the later stage. CSDS also increased the expression of NLRP1 inflammasome complexes and pro-inflammatory cytokines in a time-dependent manner. NLRP1 was found to interact with mTOR but not PI3K/AKT, and CSDS exposure enhanced this interaction. Knockdown of Nlrp1a in the hippocampus inhibited PI3K/AKT/mTOR signaling, rescued impaired autophagy, and ameliorated depressive-like behavior. Rapamycin, an autophagy inducer, abolished NLRP1 inflammasome-driven inflammatory reactions, alleviated depressive-like behavior, and exerted a neuroprotective effect. These findings suggest that autophagy dysfunction contributes to NLRP1 inflammasome-linked depressive-like behavior in mice, and regulating autophagy could be a valuable therapeutic strategy for depression. The study highlights the complex interplay between autophagy and the NLRP1 inflammasome in the pathogenesis of depression.Autophagy dysfunction contributes to NLRP1 inflammasome-linked depressive-like behaviors in mice. This study investigated the relationship between autophagy and the NLRP1 inflammasome in depression using a chronic social defeat stress (CSDS) model. The results showed that CSDS exposure caused a bidirectional change in hippocampal autophagy function, with activation in the initial period and impairment at the later stage. CSDS also increased the expression of NLRP1 inflammasome complexes and pro-inflammatory cytokines in a time-dependent manner. NLRP1 was found to interact with mTOR but not PI3K/AKT, and CSDS exposure enhanced this interaction. Knockdown of Nlrp1a in the hippocampus inhibited PI3K/AKT/mTOR signaling, rescued impaired autophagy, and ameliorated depressive-like behavior. Rapamycin, an autophagy inducer, abolished NLRP1 inflammasome-driven inflammatory reactions, alleviated depressive-like behavior, and exerted a neuroprotective effect. These findings suggest that autophagy dysfunction contributes to NLRP1 inflammasome-linked depressive-like behavior in mice, and regulating autophagy could be a valuable therapeutic strategy for depression. The study highlights the complex interplay between autophagy and the NLRP1 inflammasome in the pathogenesis of depression.