The striatal, primary sensorimotor cortical, and thalamic neurons are highly vulnerable to hypoxia-ischemia (HI) in term newborns. In a piglet model of HI that exhibits similar selective regional vulnerability, we tested the hypothesis that early treatment with sulforaphane, an activator of the Nrf2 transcription factor, protects vulnerable neurons from HI injury. Anesthetized piglets (aged 3–7 days) were subjected to 45 min of hypoxia and 7 min of airway occlusion. At 15 min after resuscitation, the piglets received intravenous vehicle or sulforaphane. At 4 days of recovery, the density of viable neurons in the putamen of vehicle-treated piglets was 31 ± 34% (±SD) that of sham-operated controls. Treatment with sulforaphane significantly increased viability to 77 ± 31%. In the sensorimotor cortex, neuronal viability was also increased; it was 59 ± 35% in the vehicle-treated and 89 ± 15% in the sulforaphane-treated animals. Treatment with sulforaphane increased the nuclear Nrf2 and γ-glu­tamylcysteine synthetase expression at 6 h of recovery in these regions. We conclude that systemic administration of sulforaphane 15 min after HI can induce the translocation of Nrf2 to the nucleus, increase expression of an enzyme involved in glutathione synthesis, and salvage neurons in the highly vulnerable putamen and sensorimotor cortex in a large-animal model of HI. Therefore, targeting Nrf2 activation soon after recovery from HI is a feasible approach for neuroprotection in the newborn brain.