〔Abstract〕 Objective To observe the pathological changes of brain tissue in neonatal rats after hypoxic-ischemic brain damage(HIBD), the distribution and expression changes of endoplasmic reticulum stress(ERS) related factors includingactivated transcription factor 6(ATF6), inositol demand factor 1(IRE1) and double-stranded RNA-activated protein kinase-likeendoplasmic reticulum kinase(PERK) in brain tissue. Methods Seven-day-old newborn rats were divided into sham operation group(Sham group) and hypoxic-ischemic brain damage group(HIBD group). The modified rice method was used to establish the HIBD model. Hematoxylin-eosin(HE) staining was performed on the brain tissue at the 72 h point of modeling to observe the pathological changes of the brain, Nissl staining was used to observe the neuron damage in the cortex and hippocampus, and immunohistochemistry was used to detect the expression of ATF6, IRE1 and PERK in the cerebral cortex and hippocampus of rats in each group. The models were sacrificed at 6 h, 24 h, and 72 h respectively, Western blot was used to detect the protein expression of ATF6, IRE1, and PERK at each time point at 6 h, 24 h, and 72 h. Results 72 hours after HIBD, HE staining showed that no nerve cell injury was observed in the Sham group, while nerve cell injury was observed in the brain tissue of the HIBD group, and the main injury sites were the cerebral cortex and hippocampus. Nissl staining showed that the proportion of damaged neurons in the cortex and hippocampus of the HIBD group was higher than that in the Sham group, and the difference was statistically significant(P<0.001). Immunohistochemical staining showed that compared with the Sham group, the number of ATF6, IRE1, and PERK positive cells(brown-yellow) in the cerebral cortex and hippocampus of the HIBD group increased(P<0.001). In the HIBD group, the expression of ATF6 in the cytoplasm and nucleus of nerve cells increased, and the expression of IRE1 in the nucleus and PERK in the cytoplasm increased. The relative protein expression levels of ATF6, IRE1, and PERK at each time point in the HIBD group were higher than those in the Sham group, and the differences were statistically significant(allP<0.05). Conclusion The brain damage of neonatal rats after hypoxic-ischemic brain injury is mainly in the cerebral cortex and hippocampus, and the expression of ER stress factors in cerebral cortex and hippocampus is increased, suggesting that ER stress related factors are involved in its pathological injury.