Cerebrovascular injury while on extracorporeal membrane oxygenation (ECMO) may be caused by excessive brain perfusion during hypoxemic reperfusion. Previous studies have postulated that the most vulnerable period of time for cerebrovascular injury is during the transfer period to ECMO. Therefore, our objective was to compare brain perfusion and hemodynamics in a piglet endotoxic shock ECMO model. The effect of ECMO flow on microcirculation of different brain regions was compared between 10 control pigs and six pigs (7–10 kg) administered IV endotoxin to achieve a drop in mean arterial blood pressure (MAP) of at least 30%. Cardiac output (CO), brain oxygen utilization, and microcirculatory blood flow (BF) were compared at baseline and 2 hours after ECMO stabilization. Matching ECMO delivery with baseline CO in control animals increased perfusion (p < 0.05) in all areas of the brain. In contrast, with endotoxin, ECMO returned perfusion closer to baseline levels in all regions of the brain and maintained brain tissue oxygen consumption. Both control and endotoxic pigs showed no evidence of acute neuronal necrosis in histologic cerebral cortical sections examined after 2 hours of ECMO. Results show that during endotoxic shock, transition to ECMO can maintain brain BF equally to all brain regions without causing overperfusion, and does not appear to cause brain tissue histopathologic changes (hemorrhage or necrosis) during the acute stabilization period after ECMO induction.