Background <p>Hypoxic–ischemic encephalopathy secondary to acute perinatal asphyxia represents a major cause of long-term neurodevelopmental impairment in children. Therapeutic hypothermia is currently considered the standard of care for term neonates with moderate to severe hypoxic–ischemic encephalopathy.</p> Objectives <p>The present study was designed to evaluate the neurodevelopmental trajectory of neonates diagnosed with moderate to severe hypoxic–ischemic encephalopathy following therapeutic hypothermia.</p> Methods <p>This prospective observational cohort study included 41 neonates with a gestational age ≥ 36 weeks and a birth weight ≥ 1.8&#xa0;kg who presented with moderate to severe hypoxic–ischemic encephalopathy. All infants underwent whole-body cooling, delivered either through active or passive methods, targeting a core temperature of 33.5&#xa0;°C (range 33–34&#xa0;°C). Surviving neonates were followed at three and six months of age to evaluate neurodevelopmental outcomes using the Bayley Scales of Infant Development.</p> Results <p>Early initiation of therapeutic hypothermia within the first 2&#xa0;h was associated with decreased mortality (<i>p</i> = 0.025). Lower Apgar score at 5&#xa0;min and hypoxic changes in cranial ultrasound were associated with increased mortality (<i>p</i> = 0.008) and (<i>p</i> = 0.014). There was no difference between active and passive cooling regarding convulsions and complications, whereas the language Bayley score at 3 months and motor Bayley score at 6 months were significantly higher in the active cooling group (<i>p</i> = 0.013, <i>p</i> = 0.022).</p> Conclusion <p>Earlier initiation of therapeutic hypothermia (first 2&#xa0;h) improves survival rate, with no difference between active and passive cooling regarding seizures and complications.</p>