Although microRNAs regulate mRNA expression intracellularly, they are often released into the circulation in inflammatory diseases. During sepsis, secreted extracellular cold‐inducible RNA‐binding protein (eCIRP) acts as a damage‐associated molecular pattern (DAMP), inducing tissue damage by elevating inflammatory cytokines and chemokines. Here, we report that the circulating microRNA 130b‐3p inhibits eCIRP‐mediated sterile and cecal ligation and puncture (CLP)‐induced non‐sterile inflammation. We find that levels of miR‐130b‐3p are increased in the serum of septic mice and patients and that it strongly interacts with recombinant murine (rm) CIRP in vitro and with eCIRP in the serum of septic mice in vivo. Combining a miR‐130b‐3p mimic with rmCIRP significantly decreases TNF‐α release by macrophages compared to only rmCIRP‐treated cells. This combined treatment also dose‐dependently decreases the affinity of rmCIRP with its receptor TLR4/MD2. Finally, injection of a miR‐130b‐3p mimic significantly reduces rmCIRP‐ or CLP‐induced systemic inflammation and acute lung injury in mice. These data show that extracellular miR‐130b‐3p functions as a novel endogenous inhibitor of eCIRP and point to an innovative therapeutic approach to treat inflammatory diseases.