Mounting evidence suggests that neurological injury occurs after deep hypothermic circulatory arrest (DHCA), a protocol widely used in surgery for congenital heart diseases and aortic repair. Neuregulin 1 (NRG1), a neurotrophic factor highly expressed in the central nervous system, is crucial for neuronal survival. However, whether NRG1 is protective against apoptosis induced by DHCA is still unclear, as are the putative mechanisms involved. In this study, exogenous human NRG1 pretreatment (2.5 and 3.75 ng/kg, intracarotid injection) significantly inhibited neuronal apoptosis in DHCA-treated male rats, and notably, endogenous NRG1 expression was also increased. Bcl-2, as well as phosphorylated phosphatidylinositol-3-kinase, Akt, and cAMP-response element binding protein, were all increased, resulting in phosphorylation and subsequent activation of the ErbB4 receptor. Finally, expression of the apoptosis-related protein cleaved-caspase-3 was decreased, resulting in the inhibition of neuronal apoptosis induced by DHCA. Thus, our data indicate that NRG1 treatment inhibited DHCA-induced neuronal apoptosis by activating ErbB4 signaling, providing a potential therapeutic pathway for the prevention of neurological injury induced by DHCA.