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There is a need to develop therapies for neonatal encephalopathy (NE) in low- and middle-income countries (LMICs) where the burden of disease is greatest and therapeutic hypothermia (HT) is not effective. We aimed to assess the efficacy of melatonin following inflammation-amplified hypoxia-ischaemia (IA-HI) in the newborn piglet. The IA-HI model accounts for the contribution of infection/inflammation in this setting and HT is not cytoprotective. We hypothesised that intravenous melatonin (5% ethanol, at 20 mg/kg over 2 h at 1 h after HI + 10 mg/kg/12 h between 24 and 60 h) is safe and associated with: (i) reduction in magnetic resonance spectroscopy lactate/N-acetylaspartate (MRS Lac/sNAA); (ii) preservation of phosphorus MRS phosphocreatine/phosphate exchange pool (PCr/Epp); (iii) improved aEEG/EEG recovery and (iv) cytoprotection on immunohistochemistry. Male and female piglets underwent IA-HI by carotid artery occlusion and reduction in FiO 2 to 6% at 4 h into Escherichia coli lipopolysaccharide sensitisation (2 μg/kg bolus + 1 μg/kg/h over 12 h). At 1 h after IA-HI, piglets were randomised to HI-saline (n = 12) or melatonin (n = 11). There were no differences in insult severity between groups. Target melatonin levels (15-30 mg/L) were achieved within 3 h and blood ethanol levels were <0.25 g/L. At 60 h, compared to HI-saline, melatonin was associated with a reduction of 0.197 log 10 units (95% CrI [-0.366, -0.028], Pr (sup) 98.8%) in basal-ganglia and thalamic Lac/NAA, and 0.257 (95% CrI [-0.676, 0.164], Pr (sup) 89.3%) in white matter Lac/NAA. PCr/Epp was higher in melatonin versus HI-saline (Pr (sup) 97.6%). Melatonin was associated with earlier aEEG/EEG recovery from 19 to 24 h (Pr (sup) 95.4%). Compared to HI-saline, melatonin was associated with increased NeuN+ cell density (Pr (sup) 99.3%) across five of eight regions and reduction in TUNEL-positive cell death (Pr (sup) 89.7%). This study supports the translation of melatonin to early-phase clinical trials. Melatonin is protective following IA-HI where HT is not effective. These data guide the design of future dose-escalation studies in the next phase of the translational pipeline., (© 2024 The Author(s). Journal of Pineal Research published by John Wiley & Sons Ltd.)