Objective To investigate the mechanism of memantine on ERK/ CREB signaling and synapticplasticity in a mouse model of cerebral ischemia-reperfusion. Methods Sixty mice were randomly divided into a shamoperation group (Sham), middle cerebral artery occlusion model group (MCAO), 20 mg/ kg memantine group (M20), 4mg/ kg memantine group (M4), and saline group (NS). With the exception of the Sham group, ischemia-reperfusion wasestablished in groups using a suture to achieve MCAO. Changes in body weight and degree of neurological deficits wereobserved in the mice. Brain atrophy volume was measured using cresyl violet staining, while sensorimotor function wasobserved by an adhesive removal test and cognitive function was detected by Morris water maze. Expression of ERK1/2,phosphorylated ERK1/2 (p-ERK1/2), CREB, p-CREB, postsynaptic density protein 95 (PSD-95) and synaptophysinwere detected by western blot assay. Results Compared with MCAO, M4, and NS groups, the M20 group exhibitedreduced weight loss, decreased neurological severity scores, decreased volume of brain atrophy, and improved sensorimotorfunction. In addition, the results of water maze testing showed that the degree of learning and memory impairment wasreduced in the M20 group. Expression of p-ERK1/2, p-CREB, PSD-95, and synaptophysin proteins were increased in theM20 group compared with other groups. Conclusions Continuous treatment with memantine (20 mg/ kg) after cerebralischemia in mice can improve the recovery of neurological function, ameliorate deficits in learning and memory, and improve synaptic plasticity of the brain.