Heart failure with preserved ejection fraction (HFpEF) is a mortal clinical syndrome without effective therapies...Supplementing HFpEF mice with nicotinamide riboside or a direct activator of NAD+ biosynthesis led to improvement in mitochondrial function and amelioration of the HFpEF phenotype. Collectively, these studies demonstrate that HFpEF is associated with myocardial mitochondrial dysfunction and unveil NAD+ repletion as a promising therapeutic approach in the syndrome.