Host immunity limits iron availability to pathogenic bacteria, but whether immunity limits pathogenic bacteria from accessing host heme, the major source of iron in the body, remains unclear. Using Citrobacter rodentium (a mouse enteric pathogen) and Escherichia coli (a major cause of sepsis in humans) as models, we find that interleukin-22 (IL-22), a cytokine best known for its ability to promote epithelial barrier function, also suppresses the systemic growth of bacteria by limiting iron availability to the pathogen. To understand the mechanistic basis of IL-22–dependent iron retention in the host, using an unbiased proteomic approach, we have identified that IL-22 induces the production of the plasma hemoglobin scavenger haptoglobin and the heme scavenger hemopexin. Moreover, the antimicrobial effect of IL-22 depends on the induction of hemopexin expression, whereas haptoglobin was dispensable. Impaired pathogen clearance in infected Il22−/− mice was restored by hemopexin administration, and hemopexin-deficient mice had increased pathogen loads after infection. These studies reveal a previously unrecognized host defense mechanism regulated by IL-22 that relies on the induction of hemopexin to limit heme availability to bacteria, leading to suppression of bacterial growth during systemic infections.