The hypothalamic paraventricular nucleus (PVN) is a specific center in the brain that regulates gastric mucosal injury following gastric ischemia‑reperfusion (GI-R) injury. This study aimed to investigate whether autophagy-lysosome dysfunction in the PVN tissues of GI-R rats is involved in the gastric injury, and the underlying molecular mechanisms. The rat model of GI-R was established by clamping the celiac artery for 30 min and reperfusion for different hours (1, 3, and 6 h). The gastric injury was evaluated by hematoxylin and eosin staining of the stomach and the gastric mucosal index. The autophagy–lysosome dysfunction in the PVN was evaluated by the protein levels of LC3 II and Beclin-1 (markers for autophagosome activity) and the activity of acid phosphatase (a representative lysosomal enzyme). Immunohistochemical staining of ionized calcium-binding adaptor molecule 1 in the PVN was performed to evaluate microglial activation. Reactive oxygen species (ROS) content and phosphorylated γ-aminobutyric acid B receptor (p-GABABR) expression in the PVN were also examined. The results revealed that, in GI-R rats, the shorter the reperfusion duration, the more severe the gastric mucosal damage. The autophagy–lysosome dysfunction exhibited by GI-R rats further enhanced microglial activation, ROS production, p-GABABR expression, and gastric injury. In addition, activating microglial cells increased ROS production, p-GABABR expression, and gastric injury in GI-R rats, while inhibiting microglial activation resulted in the opposite results. Taken together, autophagy–lysosome dysfunction induced by GI-R aggravated the gastric injury by inducing microglia activation.