Severe malaria is associated with kidney and brain injury, yet potential mechanisms linking both complications remain understudied. We investigated the associations between kidney and brain injuries in a cohort of Indian adults and children with severe Plasmodium falciparum malaria. We found that acute kidney injury was prevalent in both adults (64.4%) and children (71.4%). We also found that plasma levels of the structural kidney injury biomarker neutrophil gelatinase-associated lipocalin (NGAL) were strongly associated with acute kidney injury severity (P <.0001) and negatively correlated with whole brain magnetic resonance imaging apparent diffusion coefficient values in cerebral malaria (r = −0.6, 95% confidence interval, −0.8 to −0.3). Low apparent diffusion coefficient values indicate cytotoxic edema, a form of hypoxic brain injury mediated by parasite sequestration and inflammation. Severe cytotoxic edema has been shown to be associated with increased mortality in severe malaria. In our cohort, there was a 5.5-fold greater risk of this form of brain injury (prevalence risk ratio, 5.5, 95% confidence interval, 2.3-13.2) in patients with high NGAL levels (>300 ng/mL). These results suggest that plasma NGAL may play a critical role in structural kidney injury and could serve as a predictive marker for hypoxic brain injury in the context of severe malaria.