<p>Neonatal hypoxic-ischemic encephalopathy (HIE) is a severe neurological disorder caused by impaired cerebral blood flow and brain hypoxia, resulting in high morbidity and mortality rates. While therapeutic hypothermia remains the standard treatment and has been shown to reduce mortality to some extent, its therapeutic efficacy is limited, and it applies only to a select group of neonates who meet stringent inclusion criteria. Advances in our understanding of the pathophysiology of HIE have led to the identification of several promising neuroprotective strategies designed to mitigate or prevent the neurological damage induced by hypoxia–ischemia. Among these, preconditioning has emerged as a potent neuroprotective approach, enhancing cellular resilience to subsequent injury and potentially reducing treatment complexity and healthcare costs. Preconditioning/pretreatment and posttreatment offer significant promise in attenuating the neurological damage associated with HIE. Thus, exploring early intervention strategies for neonatal HIE, focusing on the comparative mechanisms and therapeutic targets of preconditioning and postconditioning, is critical to developing more effective treatment modalities. This review summarizes the current understanding of the pathophysiological mechanisms underlying neonatal HIE and its prevention and treatment strategies, providing new perspectives and a theoretical foundation for future neuroprotective interventions.</p>