Objective To investigate the effect of simple head cooling combined with ganglioside therapy on neonatal hypoxic-ischemic encephalopathy (HIE) and its clinical efficacy. Methods A total of 100 children with HIE admitted in the neonatal ward of our hospital from August 2018 to October 2020 were selected as the research objects, and were divided into control group and observation group according to the random number table method, with 50 cases in each group. The control group was treated with gangliosides, and the observation group was treated with simple head cooling combined with gangliosides. Observe and compare the clinical performance improvement time, the level of relevant hematological examination indexes before and after treatment, and the neonatal behavioral neurological assessment (NBNA), clinical efficacy, and adverse reactions. Results The improvement time of convulsions, disturbance of consciousness, pupil changes, hypotonia, and gastrointestinal dysfunction in the observation group was significantly lower than that in the control group (all P＜0.001). After treatment, the NSE, IL-6, CK, CK-MB of the two groups of children were significantly lower than before treatment, and the serum calcium and NBNA scores were significantly higher than before treatment, and the decrease or increase in the observation group was significantly higher than that of the control Group (all P＜0.001). The total effective rate of treatment of children in the observation group (82.00%) was higher than that of the control group (62.00%) (P