Objective To observe the clinical effect of creatine phosphate for neonates with hypoxic ischemic encephalopathy （HIE）， and the impacts on brain injury related factors and development. Methods A total of 89 children with HIE， who were admitted in our department from May 2018 to November 2019， were randomly divided into control group （n=44） and study group （n=45） by random number table method. The control group was treated with conventional treatment，the study group received creatine phosphate additionally. The treatment course was 10 days. The clinical effect， Neonatal Behavioral Neurological Assessment （NBNA） score， improvement time of clinical symptoms and serum levels of brain injury related factors （NSE and S100 protein） were compared. Mental Development Index （MDI） and Psychomotor Development Index （PDI） of the two groups after one year of treatment was evaluated， and the adverse reactions were recorded. Results The total effective rate was 93.3% （42/45） in study group， which was significantly higher than that of 77.3% （34/44） in control group （χ2 =4.601，P＜0.05）. After treatment， NBNA score （40.52±7.37）， MDI （96.2±8.3） and PDI （97.1±7.5） in study group were all higher than those of the control group ［（35.63±6.14）， （91.6±7.7） and （92.4±6.0）］ respectively， with statistically significant differences （P＜ 0.05）. The serum levels of NSE ［（26.77±3.67） μg/ml］ and S100 protein ［（1.20±0.12） μg/L］ in the study group were lower than those at baseline ［（36.01±7.65） μg/ml］， ［（1.79±0.25） μg/L］， and lower than those in the control group ［（29.10±4.72） μg/ml，（1.42±0.16） μg/L］， with statistically significant differences （P ＜ 0.05）. The improvement time of clinical symptoms in the observation group was less than that in the control group， the difference was statistically significant （P＜ 0.05）. There were no obvious adverse reactions in both groups. Conclusions Creatine phosphate could improve the effectiveness of conventional therapy for neonates with HIE.