Cardioprotection of immature hearts remains controversial and largely based on the use of hypothermic cardioplegia. Recent clinical trials in pediatric open-heart surgery suggest that normothermic cardioplegic arrest is also cardioprotective. However, the advantages of using normothermic cardioplegia delivered as single- or multi-dose with or without terminal cardioplegia are unknown. This work investigates the efficacy of these techniques and the mechanism(s) underlying their protective effect. Neonatal (7–10 days) rabbit hearts in a working mode were exposed to normothermic global ischemia (60 or 90 min) protected with one of the following cardioplegic (hyperkalaemic buffer) protocols: single-dose, multi-dose infused every 30 min, single-dose or multi-dose with terminal cardioplegia. The extent of functional recovery (e.g., aortic and coronary flow), ischemic stress (e.g., myocardial ATP, lactate) and reperfusion injury (lactate dehydrogenase (LDH) release) were assessed. Recovery following 60 min global ischemia was improved (p < 0.05) by single-dose and multi-dose cardioplegic delivery (from 5% to 60% and 80%, respectively). Improved recovery was augmented by 2 min terminal cardioplegia (to 90% and 97% for single-dose and multi-dose, respectively). Extending ischemia to 90 min with single-dose resulted in 0% recovery that was not improved by 2 min terminal cardioplegia. However, 5 min (not 10 min) terminal cardioplegia significantly improved recovery (32%). Multi-dose followed by 5 min terminal cardioplegia resulted in full recovery. Cardioprotective interventions were associated with a reduction in LDH release and attenuated changes in myocardial metabolites. During normothermic cardioplegic arrest of neonatal heart: (i) multi-dose is superior to single-dose; (ii) terminal cardioplegia confers additional protection to single-dose and multi-dose; and (iii) protection is likely to be due to metabolic preservation.