Acute ischemic stroke remains a leading cause of death and long-term disability worldwide. Although vascular recanalization restores cerebral blood flow, reperfusion can provoke excessive oxidative stress and secondary neuronal injury. Our previous study indicated lysosomal glycogen degradation was dysfunctional in astrocyte after reperfusion. However, whether pharmacological enhancement of lysosomal glycogen degradation can strengthen astrocytic antioxidant capacity during reperfusion remains unknown. Here, we investigated the neuroprotective potential of Myozyme, a recombinant acid α-glucosidase (GAA), in experimental cerebral ischemia/reperfusion. In mice subjected to middle cerebral artery occlusion/ reperfusion (MCAO/R), intravenous Myozyme administration reduced cerebral infarct volume and improved sensorimotor performance after reperfusion. In primary astrocytes subjected to oxygen-glucose deprivation/reoxygenation (OGD/R), Myozyme increased GAA activity and intracellular glucose content. These changes were accompanied by increased G6PD activity, elevated NADPH and GSH levels, and ROS accumulation. In an astrocyte-neuron coculture system, Myozymetreated astrocytes increased extracellular GSH availability and were associated with higher neuronal GSH and NADPH levels, lower neuronal ROS accumulation, and improved neuronal viability. Collectively, these findings identify Myozyme as a potential therapeutic candidate for cerebral ischemia/reperfusion injury and support a model in which increased astrocytic GAA expression is associated with enhanced PPP-related antioxidant capacity and improved redox support for neighboring neurons.