Hypoxic–ischemic (H–I) brain injury in newborns is a major cause of morbidity and mortality that claims thousands of lives each year. In this review, we summarize the promising neuroprotective agents tested on animal models and pilot clinical studies of neonatal H–I brain injury according to the different phases of the disease. These agents target various phases of injury including the early phase of excitotoxicity, oxidative stress and apoptosis as well as late-phase inflammatory reaction and neural repair. We analyze the cell survival and cell death pathways modified by these agents in neonatal H–I brain injury. We aim to ‘build a bridge’ between animal trials of neuroprotective agents and potential candidate treatments for future clinical applications against H–I encephalopathy.