['Chronic cerebral hypoperfusion is related with cognitive deficits in different types of dementia.', 'In this study, we aimed to investigate the effect and potential mechanisms of leonurine on chronic cerebral hypoperfusion both in vitro and in vivo.', 'Chronic cerebral hypoperfusion was duplicated by oxygen-glucose deprivation (OGD) in vitro and by ligation of bilateral common carotid arteries (2-VO) in vivo.', 'In in vitro study, there were control group, OGD group, OGD+\u2009100µM leonurin group, and OGD+\u200910µM donepezil group. The spontaneous excitatory postsynaptic current amplitude and frequency were recorded. In in vivo study, the chronic cerebral hypoperfusion model was induced by ligated bilateral common carotid arteries. Rats were randomly divided into Sham group, 2-VO group, 2-VO+\u200960mg/kg/day leonurine group, and 2-VO+\u20094mg/kg/day donepezil group. After three weeks, the Morris water maze and Long-term depression recording were observed. Then N-methyl-D-aspartate receptor-associated proteins and autophagy-associated proteins were detected by Western blot assay.', 'In in vitro experiment, results showed that leonurine could obviously attenuate the spontaneous excitatory postsynaptic current amplitude and frequency on pyramidal neurons. In in vivo experiment, leonurine significantly decreased levels of glutamate and hydrogen peroxide, improved both the cognitive flexibility and the spatial learning and memory abilities. Moreover, leonurine obviously enhanced long-term depression, elevated the ratio of N-methyl-D-aspartate receptor 2A/2B, and decreased the expression of postsynaptic density protein-95. Interestingly, the ratio of LC3II/LC3I and beclin-1 expression were markedly down-regulated by leonurine.'] Does leonurine ameliorate cognitive dysfunction via antagonizing excitotoxic glutamate insults and inhibiting autophagy?