Hypoxic-ischemic encephalopathy (HIE) is a devastating neurological event that contributes to the prolonged neurodevelopmental consequences in infants. Therapeutic strategies focused on attenuating neuronal apoptosis in the penumbra appears to be promising. Given the increasingly recognized neuroprotective roles of adipokines in HIE, we investigated the potential anti-apoptotic roles of a novel member of adipokines, Chemerin, in an experimental model of HIE. In the present study, 10-day-old rat pups underwent right common carotid artery ligation followed by 2.5 h hypoxia. At 1 h post hypoxia, pups were intranasally administered with human recombinant chemerin (rh-chemerin). Here, we showed that rh-chemerin prevented the neuronal apoptosis and degeneration as evidenced by the decreased expression of the pro-apoptotic markers, cleaved caspase 3 and Bax, as well as the numbers of Fluoro-Jade C and TUNEL-positive neurons. Furthermore, rh-Chemerin reversed neurological and morphological impairments induced by hypoxia-ischemia in neonatal rats at 24 h and 4 weeks after HIE. In addition, chemerin-mediated neuronal survival correlated with the elevation of chemerin receptor 23 (chemR23), phosphorylated calmodulin-dependent protein kinase kinase 2 (CAMKK2), as well as phosphorylated adenosine monophosphate-activated protein kinase (AMPK). Specific inhibition of chemR23, CAMKK2, and AMPK abolished the anti-apoptotic effects of rh-chemerin at 24 h after HIE, demonstrating that rh-chemerin ameliorated neuronal apoptosis partially via activating chemR23/CAMKK2/AMPK signaling pathway. Neuronal apoptosis is a well-established contributing factor of pathological changes and the neurological impairment after HIE. These results revealed mechanisms of neuroprotection by rh-chemerin, and indicated that activation of chemR23 might be harnessed to protect from neuronal apoptosis in HIE.