Summary Host defenses against pathogens are energetically expensive, leading ecological immunologists to postulate that they might participate in energetic trade-offs with other maintenance programs. However, the metabolic costs of immunity and the nature of physiologic trade-offs it engages are largely unknown. We report here that activation of immunity causes an energetic trade-off with the homeothermy (the stable maintenance of core temperature), resulting in hypometabolism and hypothermia. This immunity-induced physiologic trade-off was independent of sickness behaviors but required hematopoietic sensing of lipopolysaccharide (LPS) via the toll-like receptor 4 (TLR4). Metabolomics and genome-wide expression profiling revealed that distinct metabolic programs supported entry and recovery from the energy-conserving hypometabolic state. During bacterial infections, hypometabolic states, which could be elicited by competition for energy between maintenance programs or energy restriction, promoted disease tolerance. Together, our findings suggest that energy-conserving hypometabolic states, such as dormancy, might have evolved as a mechanism of tissue tolerance. Graphical Abstract Highlights • Activated immunity engages in an energetic trade-off with homeothermy • Immunity reprograms hepatic metabolism to meet host energetic priorities • Energetic trade-off between immunity and homeothermy promotes disease tolerance • Hypometabolic states promote disease tolerance during bacterial infections Immune activation after infection is metabolically costly, competing for energy with the maintenance of normal body temperature, and this dynamic trade-off leads to preferential use of tolerance as a mechanism of bacterial defense. [ABSTRACT FROM AUTHOR]