(1) Birth asphyxia is a major cause of delivery room resuscitation. Subsequent organ failure and hypoxic–ischemic encephalopathy (HIE) account for 25% of all early postnatal deaths. The neonatal sequential organ failure assessment (nSOFA) considers platelet count and respiratory and cardiovascular dysfunction in neonates with sepsis. To evaluate whether nSOFA is also a useful predictor for in-hospital mortality in neonates (≥36 + 0 weeks of gestation (GA)) following asphyxia with HIE and therapeutic hypothermia (TH), (2) nSOFA was documented at ≤6 h of life. (3) A total of 65 infants fulfilled inclusion criteria for TH. All but one infant received cardiopulmonary resuscitation and/or respiratory support at birth. nSOFA was lower in survivors (median 0 [IQR 0–2];n= 56, median GA 39 + 3, femalen= 28 (50%)) than in non-survivors (median 10 [4–12],p< 0.001;n= 9, median GA 38 + 6,n= 4 (44.4%)). This was also observed for the respiratory (p< 0.001), cardiovascular (p< 0.001), and hematologic sub-scores (p= 0.003). The odds ratio for mortality was 1.6 [95% CI = 1.2–2.1] per one-point increase in nSOFA. The optimal cut-off value of nSOFA to predict mortality was 3.5 (sensitivity 100.0%, specificity 83.9%). (4) Since early accurate prognosis following asphyxia with HIE and TH is essential to guide decision making, nSOFA (≤6 h of life) offers the possibility of identifying infants at risk of mortality.