Ketone bodies are the product of lipid metabolism and can serve as an alternative energy source to glucose during cerebral respiration. Acute brain injury, including trauma and other insults such as cerebrovascular accidents, results in dysfunctional glucose metabolism that can further promote oxygen radical formation and cell death. Ketone supplementation provides an alternate energy source to glucose that may minimize inflammation by altering the concentration of intracellular metabolites and optimize energy production in dysfunctional neurons. Inducing ketosis is challenging in critically ill patients. Conventional approaches with dietary modification, the ketogenic diet, are limited due to the time taken to induce ketosis. Alternative exogenous supplements, such as oral ketone esters and intravenous beta-hydroxybutyrate formulations, provide supratherapeutic concentrations of ketone bodies within hours of administration. Such formulations reduce the cerebral infarct volume and improve energy production in animal models of brain injury. Human studies remain lacking.