Acute ischemic stroke is one of the leading causes of death in developed countries and the most common cause of disability in adults worldwide. Despite advances in the understanding of stroke pathophysiology, therapeutic options remain limited. In this study, we explored the interaction of Shrm4 and the metabotropic gamma-aminobutyric acid (GABA) receptors (GABA ) in ischemic stroke. A transient middle cerebral artery occlusion (MCAO) model was induced by filament insertion in Shrm4+/+ and wild-type C57BL/6J mice, followed by reperfusion for up to 7 days. Baclofen was administered was used to activate GABA in vivo during reperfusion. Neurological deficits, motor and memory functions, and infarct volume were determined in the various mouse groups. Furthermore, we also developed an oxygen-glucose deprivation (OGD) cell model in primary neurons to test Shrm4/GABA interactions in vitro. Shrm4 was observed to decrease infarct volume and neuronal cell loss in penumbra, and rescue neurological deficits in MCAO mice. Notably, Shrm4 also increased pole climbing speed, reduced foot faults, and increased escape latency in the Morris water maze test, while reducing neuron autophagy through an interaction with GABA receptors. GABA activation using baclofen further reduced OGD-induced neuron damage in culture and stroke outcomes of MCAO, relative to Shrm4 alone. Taken together, Shrm4-mediated GABA activation confers neuroprotection by reducing neuronal autophagy in acute ischemic stroke.