This study investigates the role of autophagy dysfunction in NLRP1 inflammasome-linked depressive-like behaviors in mice. Chronic social defeat stress (CSDS) was used to induce depressive-like behaviors, and the effects on autophagy were assessed. The results show that CSDS causes a bidirectional change in autophagy function, initially activating autophagy but impairing it later. The expression of NLRP1 inflammasome complexes and pro-inflammatory cytokines increased over time, while the PI3K/AKT/mTOR signaling pathway was also activated. NLRP1 was found to interact with mTOR but not PI3K/AKT, and CSDS facilitated this interaction. Knocking down Nlrp1a in the hippocampus inhibited the PI3K/AKT/mTOR signaling pathway, rescued autophagy impairment, and ameliorated depressive-like behaviors. Additionally, rapamycin, an autophagy inducer, abolished NLRP1-driven inflammatory responses, alleviated depressive-like behavior, and exhibited neuroprotective effects. These findings suggest that autophagy dysfunction contributes to NLRP1 inflammasome-linked depressive-like behaviors in mice, and regulating autophagy could be a valuable therapeutic strategy for depression.This study investigates the role of autophagy dysfunction in NLRP1 inflammasome-linked depressive-like behaviors in mice. Chronic social defeat stress (CSDS) was used to induce depressive-like behaviors, and the effects on autophagy were assessed. The results show that CSDS causes a bidirectional change in autophagy function, initially activating autophagy but impairing it later. The expression of NLRP1 inflammasome complexes and pro-inflammatory cytokines increased over time, while the PI3K/AKT/mTOR signaling pathway was also activated. NLRP1 was found to interact with mTOR but not PI3K/AKT, and CSDS facilitated this interaction. Knocking down Nlrp1a in the hippocampus inhibited the PI3K/AKT/mTOR signaling pathway, rescued autophagy impairment, and ameliorated depressive-like behaviors. Additionally, rapamycin, an autophagy inducer, abolished NLRP1-driven inflammatory responses, alleviated depressive-like behavior, and exhibited neuroprotective effects. These findings suggest that autophagy dysfunction contributes to NLRP1 inflammasome-linked depressive-like behaviors in mice, and regulating autophagy could be a valuable therapeutic strategy for depression.