ABSTRACT Brain injury from neonatal hypoxia-ischemia (HI) in the term and preterm newborn often results in chronic neurological and developmental disability and yet, only limited therapies are available for its prevention and treatment. Human chorionic gonadotropin (hCG) is a placentally derived hormone with biological properties that make it suitable for its use in neuroprotection of the injured newborn brain. hCG structurally and functionally acts as an immunomodulating neurotrophin protein, enhancing the survival, growth and differentiation of immature neurons. Furthermore, hCG receptors are found in the fetal nervous system and hCG itself can cross the blood brain barrier and enter the brain. We also find that peripheral intraperitoneal administration of this hormone protects the newborn mouse brain against the effect of HI. Furthermore, direct exposure of hCG to immature injured neurons increases their survival and growth and protects them against glutamate receptor-mediated excitotoxicity. However, little is known about hCG’s maximal neuroprotective efficacy, safety and the cellular mechanisms responsible its anti-degenerative effects. Furthermore, the function of brain hCG receptors in the healthy and diseased developing brain remains unknown. To address this concern, we propose to use biochemical, molecular, histological, behavioral and neurophysiological methods to explore the neuroprotective function of hCG and hCG receptors in a mouse model of preterm and term brain injury. The central hypothesis of this project is that central hCG receptor activation by hCG in the injured term and preterm mouse brain reduces cerebral dysfunction and decreases neuronal degeneration via a PKA/ERK-mediated pathway. This research can serve as a translatable platform for the development of hCG and/or its mechanisms in the prevention and treatment of the devastating neurological effects brought on by neonatal cerebral injury.