Oxygen therapy used in the treatment of perinatal hypoxia induces neurodegeneration in babies with immature antioxidant mechanisms. Zonisamide is a new antiepileptic drug used in childhood intractable seizures. Many studies demonstrated its neuroprotective effects. There is no study evaluating its effect on hyperoxic brain injury. The aim of this study was to investigate the neuroprotective effect of zonisamide on hyperoxia-induced neonatal brain injury. A total of 21 Wistar rat pups were used. The animals were divided into three groups: control group, hyperoxia group, and zonisamide-treated group. The zonisamide-treated group received an intraperitoneal injection of zonisamide. Zonisamide significantly preserved the number of neurons in CA1 and dentate gyrus parts of hippocampus, prefrontal, and parietal cortex. Zonisamide treatment also decreased the number of apoptotic neurons in all examined parts of hippocampus, prefrontal, and parietal cortex. We suggest that zonisamide treatment may be used as a neuroprotective agent in hyperoxic brain injury.