Acute brain injury (ABI) increases morbidity and mortality in patients with veno-arterial extracorporeal membrane oxygenation (VA-ECMO). Optimal neurologic monitoring methods have not been well-explicated. We studied the use of Near-infrared Spectroscopy (NIRS) to monitor cerebral regional oxygenation tissue saturation (rSO2) and its relation to ABI in VA-ECMO. In this prospective, observational cohort study of 39 consecutive patients, we analyzed the ability of rSO2 values from continuous bedside NIRS monitoring to predict ABI during VA-ECMO support. ABI occurred in 24 (61.5%) patients. Those with ABI had a lower pre-ECMO Glasgow Coma Scale, more blood product transfusions of pRBCs and FFP, and higher APACHEII score. Baseline rSO2 values were not significantly different between cohorts (54.25 vs 58.50, p = 0.260), while the minimum rSO2 value was lower for patients who experienced an ABI than those who did not (39.75 vs 44.50, p = 0.039). In patients with ABI, 21 (87.5%) had a drop in rSO2 of 25% from baseline, compared to only 7 (46.7%) patients without ABI (p = 0.017). By ROC analysis, we found that desaturations with >25% drop from the baseline rSO2 on VA-ECMO exhibited 86% sensitivity and 55% specificity to predict ABI, with an area under the curve of 0.68. Patients with ABI were more likely to have withdrawal of life sustaining therapy (17 vs 5, p = 0.049), while neurologic outcome and mortality were not statistically different between patients with or without ABI. Our results support that cerebral NIRS is a useful, real-time bedside neuromonitoring tool to detect ABI in VA-ECMO patients. A >25% drop from the baseline was sensitive in predicting ABI occurrence. Further research is needed to assess how to implement this knowledge to utilize NIRS in developing appropriate intervention strategy in VA-ECMO patients.