Neonatal hypoxic-ischemic encephalopathy (HIE) is a severe brain lesion caused by perinatal asphyxia that often results in neonatal death or long-term neurological deficits. The in-depth study of cell death mechanisms has recently led to the discovery of cuproptosis, a new type of cell death. Although understanding the relationship between HIE and cuproptosis is still in its preliminary stages, there is evidence that copper ions and their associated metabolic pathways play an important role in the pathophysiology of HIE. We used the Rice-Vannucci method to construct a mouse model of HIE. Cerebral infarct volume was measured by 2,3,5-triphenyltetrazolium chloride staining and pathological changes in brain tissue were examined by hematoxylin and eosin and Nissl staining. The levels of cuproptosis indicators and of key proteins, Copper Metabolism MURR1 domain protein 1 (COMMD1) and ATPase Copper Transporting Alpha (ATP7A), in the signaling axis related to cuproptosis were determined by western blotting. Mitochondrial morphology was observed by transmission electron microscopy, and copper salt staining and a copper ion probe were used to detect copper ion levels. Methyl thiazolyl tetrazolium (MTT) assays were used to measure neuronal survival. Our results indicate that cuproptosis occurs during neonatal ischemia and hypoxia, and that cuproptosis can regulate the occurrence and development of neonatal ischemic-hypoxic encephalopathy through the COMMD1/ATP7A signaling axis. This study provides new understanding of neonatal ischemic-hypoxic encephalopathy and indicates targets for the development of therapeutics.