Birth asphyxia is associated with disturbed development of the neonatal brain. In this study, we determined if low-dose melatonin (0.1 mg/kg/day), administered to the mother over 7 days at the end of pregnancy, could protect against the effects of birth asphyxia in a precocial species – the spiny mouse (Acomys cahirinus). At 37 days of gestation (term is 38–39 days), pups were subjected to birth asphyxia (7.5 min uterine ischemia) and compared to Cesarean section-delivered controls. At 24 h of age, birth asphyxia had increased markers of CNS inflammation (microglia, macrophage infiltration) and apoptosis (activated caspase-3, fractin) in cortical gray matter, which were reduced to control levels by prior maternal melatonin treatment. Melatonin may be an effective prophylactic agent for use in late pregnancy to protect against hypoxic-ischemic brain injury at birth.