Diabetes is a risk factor for myocardial infarction, and outcomes after myocardial infarction are worse among diabetics compared with nondiabetics. Diabetes is associated with impaired Heme clearance. Here, we determined whether heme toxicity and impaired heme clearance contribute to diabetic myocardial infarction injury and assessed IL-10 as a therapeutic agent for diabetic myocardial infarction. Plasma-free hemoglobin was significantly elevated in diabetic mice compared with nondiabetic mice after myocardial infarction. Infarct size had strong correlation to the level of plasma-free hemoglobin. Hemoglobin and reactive iron deposition within the infarct zone were also demonstrated in diabetic MI. IL-10 significantly reduced infarct size and improved cardiac function in diabetic mice. Moreover, IL-10 improved capillary density, reduced apoptosis, and decreased inflammation in the border zone of the infarcted hearts, findings that were partially inhibited by Tin protoporphyrin (a heme oxygenase-1 inhibitor). IL-10 upregulated CD163, the hemoglobin:haptoglobin scavenger receptor, and heme oxygenase-1 in THP-1-derived and primary human CD14+ macrophages. IL-10 significantly protected against ischemic injury when HL-1 cardiomyocytes were cotreated with hemoglobin. Together, our findings indicate that IL-10 is cardioprotective in diabetic myocardial infarction via upregulation of heme clearance pathways. These findings implicate heme clearance as a potentially novel therapeutic direction for diabetic myocardial infarction.