Neonatal hypoxic ischemic encephalopathy (Neonatal HIE) is a common but serious disease caused by perinatal asphyxia injury in newborns. Elevated neuronal apoptosis plays an important role in the injury process post hypoxia ischemia of the brain, which accurate mechanism is still worthy to be studied. Cellular repressor of E1A-stimulated genes (CREG) possesses the protective effect in ischemia-reperfusion in multiple organs, including livers and hearts. The main purpose of this work was to investigate whether CREG was involved in alleviating neonatal HIE and explore the possible mechanisms. We found that CREG expression was downregulated in the hippocampus of neonatal HIE rats as well as oxygen-glucose deprivation/reperfusion (OGD/R)-treated hippocampal neurons. Besides, CREG overexpression promoted survival while inhibited apoptosis in OGD/R-induced hippocampal neurons accompanied by AKT signaling activation, which could be reversed by CREG silence. In addition, the protective effects of CREG overexpression could be antagonized by AKT deactivation, indicating the function of CREG was attributed by regulating AKT pathway. Collectedly, we demonstrated that CREG protected hippocampal neurons from hypoxic ischemia-induced injury through regulating survival and apoptosis via activating AKT signaling pathway.