Vascular endothelial growth factor (VEGF) has recently been proved to be a potential therapeutic drug in ischemic disorders depending on the dose, route and time of administration, especially in focal cerebral ischemia. Whether VEGF could exert protection in a long-term total cerebral ischemic model is still uncertain, and the cellular mechanism has not been clarified so far. In order to answer the above issue, an experiment was performed in non-invasively giving exogenous VEGF to a total cerebral ischemic model rats and examining their spatial cognitive function by performing Morris water maze and long-term potential test. Moreover, we performed in vitro experiment to explore the cellular mechanism of VEGF protection effect. In an in vitro ischemia model oxygen-glucose deprivation (OGD), whole-cell patch-clamp recording was employed to examine neuronal function. Additionally, hematoxylin-eosin and propidium iodide staining were applied in vivo and in vitro in the neuropathological and viability study, separately. Our results showed that intranasal administration of VEGF could improve the cognitive function, synaptic plasticity and damaged hippocampal neurons in a global cerebral ischemia model. In addition, VEGF could retain the membrane potential, neuronal excitability and spontaneous excitatory postsynaptic currents in the early stage of ischemia, which further demonstrated that there was an acute effect of VEGF in OGD-induced pyramidal neurons. Simultaneously, it was also found that the death of CA1 pyramidal neuronal was significantly reduced by VEGF, but there was no similar effect in VEGF coexists with SU5416 group. These results indicated that VEGF could ameliorate cognitive impairment and synaptic plasticity via improving neuronal viability and function through acting on VEGFR-2.