Significance Interleukin 1 family member IL-37 is a naturally occurring inhibitor of inflammation. In this study, exogenous administration of recombinant human IL-37 reversed the decrease in exercise performance observed during systemic inflammation. IL-37 also increased exercise performance in healthy mice. IL-37 treatment acted through a dual mechanism of suppression of inflammation and modulation of metabolic pathways. The implications of the present findings impact on patients with chronic inflammatory diseases spanning from rheumatoid arthritis to cancer, in which fatigue is often incapacitating, and provide rationale for exploring recombinant IL-37 in the treatment of inflammation-mediated fatigue.