Tissue‐resident cardiac macrophage subsets mediate cardiac tissue inflammation and repair after acute myocardial infarction (AMI). CC chemokine receptor 2 (CCR2)‐expressing macrophages have phenotypical similarities to M1‐polarized macrophages, are pro‐inflammatory, and recruit CCR2 ⁺ circulating monocytes to infarcted myocardium. Small extracellular vesicles (sEV) from CCR2 ^̶ macrophages, which phenotypically resemble M2‐polarized macrophages, promote anti‐inflammatory activity and cardiac repair. Here, the authors harvested M2 macrophage‐derived sEV (M2 _EV ) from M2‐polarized bone‐marrow‐derived macrophages for intramyocardial injection and recapitulation of sEV‐mediated anti‐inflammatory activity in ischemic‐reperfusion (I/R) injured hearts. Rats and pigs received sham surgery; I/R without treatment; or I/R with autologous M2 _EV treatment. M2 _EV rescued cardiac function and attenuated injury markers, infarct size, and scar size. M2 _EV inhibited CCR2 ⁺ macrophage numbers, reduced monocyte‐derived CCR2 ⁺ macrophage recruitment to infarct sites, induced M1‐to‐M2 macrophage switching and promoted neovascularization. Analysis of M2 _EV microRNA content revealed abundant miR‐181b‐5p, which regulated macrophage glucose uptake, glycolysis, and mitigated mitochondrial reactive oxygen species generation. Functional blockade of miR‐181b‐5p is detrimental to beneficial M2 _EV actions and resulted in failure to inhibit CCR2 ⁺ macrophage numbers and infarct size. Taken together, this investigation showed that M2 _EV rescued myocardial function, improved myocardial repair, and regulated CCR2 ⁺ macrophages via miR‐181b‐5p‐dependent mechanisms, indicating an option for cell‐free therapy for AMI.