Objective To explore the influence of edaravone on cerebral edema in neonatal rats with hypoxicischemicencephalopathy (HIE) and on the CD163/ HO-1 signaling pathway. Methods A total of 120 SD neonatal rats (7days old) were included here, 90 of which underwent double ligation of the proximal and distal ends the left commoncarotid artery to establish a hypoxic-ischemic brain damage (HIBD) model. After ligation and hypoxia the rats were thendivided into a model group and an edaravone group. The remaining 30 rats had only separated the common carotid arterywithout ligation as a sham operation group. The rats in the edaravone group were immediately intraperitoneally injected with2 mg/ kg edaravone after model establishment, once a day for 5 consecutive days. The model group and the sham operationgroup were given the same amount of saline intraperitoneally at the same time. After operation, the biological behaviors ofthe neonatal rats were observed. After modeling for 24 h,the morphology of brain tissue in neonatal rats was observed byTTC staining. Changes of the water content in brain tissue of neonatal SD rats were detected at 6, 12, and 24 h, and 2, 3,and 5 days after model establishment. CD163 and HO-1 mRNA expression levels were determined by quantitativefluorescence PCR (qRT-PCR). CD163 and HO-1 protein expression levels were tested using western blotting. Results After operation, 90 neonatal rats showed lethargy, malaise, and convulsions. Those symptoms were clearly alleviated aftertreatment with edaravone compared with those in the model group, and improved within 3 days. At 24 h after modelestablishment, TTC staining showed that the left hemisphere was edematous and had a pale color in the model group, andalso had a slightly larger volume than the right hemisphere. The degree of injury of brain tissue significantly decreased afteredaravone treatment. The infarct size in the left hemisphere of the rats in the model group and the edaravone group wassignificantly greater than that in the sham operation group ( P < 0. 05), and the infarct size in the edaravone-treated groupwas significantly smaller than that in the model group ( P < 0. 05). At 6 h after modeling, water contents of brain tissue inthe model group and edaravone group were significantly higher than that in the sham operation group ( P < 0. 05), and brainwater content was the highest at 2 days. The water content in brain tissue of neonatal rats treated with edaravone wassignificantly lower than that in the model group ( P < 0. 05). qRT-PCR and western blotting showed that CD163 and HO-1mRNA/ protein expression levels in brain tissue of neonatal rats in the model group and edaravone group were significantlyincreased compared with those in the sham operation group ( P < 0. 05). CD163 and HO-1 mRNA/ protein expression levelsin neonatal rats were significantly higher than those in the model group after edaravone treatment ( P < 0. 05). Conclusions Edaravone can clearly reduce the degrees of cerebral edema and cerebral infarction in neonatal rats with HIBD. The mechanism behind this may be related to activation of the CD163/ HO-1 signaling pathway.