Iron regulatory protein 1 (IRP1) is a post-transcriptional regulator of cellular iron metabolism. Irp1-/- mice are viable but develop polycythemia. We report that these animals also exhibit fasting hypoglycemia and are protected against high fat diet-induced hyperglycemia and liver steatosis. Mechanistically, proteomics analysis revealed mitochondrial dysfunction in Irp1-/-livers. Seahorse assays validated impaired respiratory capacity in primary hepatocytes but also differentiated myotubes from Irp1-/- mice, which caused a switch from oxidative phosphorylation to glycolytic metabolism for energy production. This was accompanied by increased insulin sensitivity and glucose uptake by skeletal muscles. However, under conditions of metabolic stress or iron restriction, IRP1 deficiency prevented appropriate mitochondrial iron supply. Mitochondrial dysfunction and inefficient energy production caused metabolic rewiring and accumulation of metabolites in skeletal muscles of Irp1-/- mice, making them unavailable for gluconeogenesis in the liver. Thus, IRP1 emerges as an important metabolic regulator.