Unbalanced immune responses to invading pathogens can be life-threatening. Therefore, understanding the underlying regulatory mechanisms remains crucial. Here, we show a HIF-1α-dependent miR-210 upregulation in monocytes and macrophages upon pathogen interaction. Genetic ablation of miR-210 in the hematopoietic lineage or in monocytes/macrophages mitigated the symptoms of endotoxemia, bacteremia, sepsis and parasitosis, limiting the cytokine storm, organ damage/dysfunction, pathogen spreading and lethality. Pharmacologic miR-210 inhibition improved the survival of septic mice, too. Mechanistically, miR-210 induction in activated macrophages supported a switch towards the pro-inflammatory, M1 state by tuning down mitochondria respiration in favor of glycolysis, partly achieved by downmodulating the Iron-Sulfur Cluster assembly enzyme ISCU. In humans, augmented miR-210 levels in circulating monocytes correlated with the incidence of sepsis, while serum levels of monocyte/macrophage-derived miR-210 were associated with sepsis mortality. Altogether our data identify miR-210 as a fine-tuning regulator of macrophage metabolism and inflammatory responses paving the way towards miR-210-based therapeutic and diagnostic strategies.