Highlights • Inhaled hydrogen gas has been shown to temper the sequelae of ischemic insults. Its application in cardiopulmonary bypass has not been investigated. • Neonatal swine were cannulated to cardiopulmonary bypass and exposed to prolonged circulatory arrest (75 min at 25°C). Swine were randomized to treatment with or without inhaled 2.4% hydrogen gas mixtures for 24 h during and following ischemic injury. Hydrogen-treated swine exhibited significantly less severe brain injury than controls, as quantified by clinical examination, serology, magnetic resonance-graded volume of injury, and histopathology. Hydrogen treatment also decreased renal injury. • The administration of inhaled 2.4% hydrogen gas mixtures through a standard ventilator and anesthesia machine were safe, even in the setting of electrocautery.