Abstract Sickness behaviors, including anorexia, are evolutionarily conserved responses to acute infections. Inflammation-induced anorexia causes dramatic metabolic changes, of which components critical to survival are unique depending on the type of inflammation. Glucose supplementation during the anorectic period induced by bacterial inflammation suppresses adaptive fasting metabolic pathways, including fibroblast growth factor-21 (FGF21), and decreases survival. Consistent with this observation, FGF21 deficient mice are more susceptible to mortality from endotoxemia and poly-bacterial peritonitis, but not viral infection. Here we report that increased circulating FGF21 during bacterial inflammation is hepatic-derived, promotes cardiac function, and is required for survival. FGF21 signaling downstream of its obligate co-receptor beta-Klotho (KLB) is required. However, mice with central nervous system or adipose-specific deletion of Klb do not demonstrate any difference in response to bacterial inflammation, suggesting that multiple tissues and/or a novel FGF21 target tissue are required for the full protective effect of FGF21. These data suggest that hepatic FGF21 is a novel cardioprotective factor in bacterial sepsis. eTOC Summary In response to bacterial inflammation, hepatic fibroblast growth factor 21 (FGF21), an endocrine hormone that mediates adaptive responses to metabolic stresses such as starvation, promotes survival by supporting heart function.