Acute systemic inflammatory response induced by bacterial products, such as lipopolysaccharide (LPS), results in dramatic changes in organismal physiology that can culminate in death. Multiple factors can contribute to endotoxemia-associated mortality, including direct inflammatory damage to vital organs, hemodynamic shock, and multiple organ failure1. Here, we explored the role of brain-body communication in the setting of acute systemic inflammatory response. We found that the common anesthetic drug, ketamine, prevented LPS-induced mortality. Ketamine also prevented death from direct TNF-administration, suggesting that survival was not depended solely on lowering systemic cytokines. Detailed systemic profiling reveals that ketamine induced a neuroprotective state characterized by restored heat production, preserved arousal networks, and faster recovery from systemic hypometabolism sixteen hours after treatment. Importantly, peripheral administration of a blood–brain barrier (BBB)–impermeant NMDA antagonist analog does not prevent death. Conversely, central administration of the same analog mimics the survival benefit of systemic ketamine, demonstrating that the NDMA antagonism in the CNS is sufficient to protect mice from LPS-induced mortality. These findings suggest a brain-to-body survival circuit, which restores metabolic balance and impacts survival after inflammatory shock. Our research redefines ketamine’s mechanism of action, positioning it as a key neuroimmune modulator at the CNS that transforms a deadly metabolic collapse into a recoverable physiological state.