Hypoxic-ischemic encephalopathy is a frequent and unexpected birth complication causing major neurological disorders in newborn infants. Our goal was to elaborate a standardized protocol of hypoxia-ischemia in piglets for the further evaluation of innovating cardio- and neuroprotective strategies. Newborn piglets were anesthetized and submitted to 30 min of hypoxia (FiO 2 = 10%) followed by ischemia induced by 7 minutes of respiratory arrest (HI group). Cardiopulmonary resuscitation was instituted through external cardiac massage and epinephrine administration (4 μg/kg, i.v.). Another group of piglets was submitted to a Sham procedure with neither hypoxia nor ischemia. In both groups, animals were maintained under mechanical ventilation during 6 hours. After weaning, survival and neurological dysfunction were assessed during 7 days. Animals were then euthanized and histologic damage was assessed in the brain (HE and fluorojade-B staining). Eight and four animals were submitted to HI or Sham procedure, respectively. In the HI group, a severe bradycardia and hypotension was observed at the end of the ischemic period (mean arterial pressure = 28 ± 2 vs. 59 ± 3 mmHg in HI vs. Sham, respectively; P < 0.05). Animals from the HI group presented marked metabolic acidosis and lactate levels elevation (e.g., 18.0 ± 1.3 vs. 8.1 ± 0.7 mmol/L for lactates levels at t = 30 min post-ischemia in HI vs. Sham, respectively; P < 0.05). In the HI group, three piglets died prematurely from post-hypoxic complications and four piglets were euthanized due to severe neurological dysfunction. Only one piglet survived to the end of the protocol in this group, whereas all piglets survived without neurological sequelae in the Sham group. Severe histologic damages were observed in the brain in HI animals, consistent with the clinical neurological dysfunction. This model is suitable for the evaluation of new protective therapies after neonatal asphyxia.