Immediate iron restriction by the host is a critical process to protect against bacterial infections. Although the cell-dependent iron sequestration mechanism in liver or spleen has been identified, it is still unclear that whether the host launched humoral regulation mechanism to promptly acquire iron that widely distributes throughout body fluids. Here, we showed that after bacterial invasion, host immediately releases nanosized exosomes to capture circulating iron-containing proteins, which is required for prompt systemic iron sequestration and antibacterial defense. Mechanistically, in a sepsis model, we found that Salmonella Typhimurium induces endoplasmic reticulum stress in macrophages and activates inositol requiring enzyme 1α (IRE1α) signaling, triggering lysosomal dysfunction and promoting exosome release. These exosomes bearing transferrin receptors, CD163 and CD91 bind multiple iron-containing proteins, prevent bacteria from iron acquisition, and recycle them to tissue-resident macrophages, ultimately sequestering iron and protecting against infection. Our findings reveal a previously unknown humoral regulation mechanism of iron metabolism during bacterial infection, and suggest the release and circulation of extracellular vesicles could be an important way to promptly regulate systemic ion metabolism.