Inhaled general anesthetics are used commonly in adults and children, and a growing body of literature from animals and humans suggests that exposure to anesthesia at an early age can impact brain development. While the origin of these effects is not well understood, it is known that anesthesia can disrupt oxygen regulation in the brain, which is critically important for maintaining healthy brain function. Here we investigated how anesthesia affected brain tissue oxygen regulation in neonatal rabbits by comparing brain tissue oxygen and single unit activity in the awake and anesthetized states. We tested two common general anesthetics, isoflurane and sevoflurane, delivered in both air and 80% oxygen. Our findings show that general anesthetics can greatly increase brain tissue PO2 in neonates, especially when combined with supplemental oxygen. Although isoflurane and sevoflurane belong to the same class of anesthetics, notable differences were observed in their effects upon neuronal activity and spontaneous respiration. Our findings point to the need to consider the potential effects of hyperoxia when supplemental oxygen is utilized, particularly in children and neonates.