Objective To improve the classic Vannucci method for establishing a model of hypoxic-ischemic brain damage in the neonatal mice. Methods Postnatal day 11 KM mice were randomly assigned into normal control group (N group, n=20) and hypoxic-ischemic brain damage group (HIBD group, n=160). For the HIBD group, the left common carotid artery of mice was ligated and exposed to hypoxia according to different conditions in the groups C1-C8, then compared the mortality and the success rates of all groups. TTC staining and relative infarct volume was measured to select the most stable conditions of modeling. In all groups, the growth and development of mice were evaluated by body weight growth curve at different time points after modeling. Longa test, grip test and hanging test were porformed to assess the neuromotor function. HE staining was used to detect cerebral neuronal pathological changes.Results Neonatal mouse models of hypoxic-ischemic brain damage were established by the left common carotid artery ligation and hypoxia for 45 min under conditions of 8% O₂ and 35℃, which resulted a low mortality rate (8.3%) and high success rate (47.92%). Compared with the normal group, mice of the HIBD group grew slowly in body weight and showed severe motor dysfunction. The ligation side of cerebral artery showed infarction area which accounted for 7.76±0.70% of the total brain. The cortex and hippocampus of ligated brain tissue showed neuron degeneration and necrosis.Conclusions The neonatal mouse model of hypoxic-ischemic brain damage is successfully established by our modified method, i.e. to ligate the left common carotid artery and to expose the mice to hypoxia at 8% O₂ and 35℃ for 45 min. This model provides a liable and stable experimental animal model for research of neonatal hypoxic-ischemic brain damage.