Approximately 18 million people die of cardiovascular disease (CVD) around the world each year, making CVDs the number one cause of death in the world1. The extracellular signal-regulated protein kinase 5 (ERK5) has been found to play an essential role in cell growth and survival in heart disease, however, its role in other cell functions is still under investigation. Therefore, the objective of this study was to uncover the potential participation of ERK5 in cardiac metabolism, particularly under pathological conditions. In the setting of high-fat diet (HFD)-induced obesity, it was demonstrated that ERK5 regulates peroxisome proliferator-activated receptor gamma co-activator alpha (PGC1alpha) expression through myocyte enhancer factor 2 a (MEF2A) and MEF2D, this way maintaining mitochondrial biogenesis, fatty acid oxidation (FAO), and oxidative stress control. Mimicking HFD stress, saturated fatty acid treatment in adult rat cardiomyocytes (ARCMs) showed that the oxidative stress produced by GP91PHOX activates calpain1, which degrades ERK5. Preventing ERK5 loss by Gp91phox or Calpain- 1 inhibition preserved mitochondrial function and FAO. Similarly, restoring ERK5 expression in ERK5-deficient hearts using adeno-associated virus 9 (AAV9) prevented the development of heart failure after HFD feeding. In the context of myocardial infarction (MI), it was established that ERK5 loss leads to a dampened cardiac insulin response, increased apoptosis and accelerated cardiac dysfunction through an increased inhibition of the insulin receptor substrate 1 (IRS1) by miR128-3p. Subjecting ARCMs and human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) to hypoxia, it was discovered that ERK5 regulates miR128-3p by activation of the CAMP responsive element binding protein (CREB)-CCAAT/enhancer-binding protein beta (CEBPbeta) pathway. Consistent with these observations, ERK5 restoration, CEBPbeta overexpression, or miR128-3p inhibition in ERK5-deficient mice by AAV9 injection normalized IRS1 level and cardiac function after MI. These results indicate that the ERK5-CEBPbeta pathway is essential for the prevention of insulin resistance after an ischaemic insult by protecting IRS1. ERK5 was found to be a cardioprotective regulator of lipid and glucose metabolism under stress; therefore, indicating its potential as a treatment to prevent heart failure.