The metabolic flexibility of tissues determines the degree and reversibility of organ damage during inflammatory challenges. However, effective treatments for myocardial metabolic dysfunction in septic cardiomyopathy (SCM) are unavailable. Nicotinamide adenine dinucleotide-dependent signaling is fundamental to cellular metabolic homeostasis and inflammatory responses. Here, using male mice models, we reveal that both genetic and pharmacological inhibition of mono-ADP-ribosyl hydrolase MacroD1 which is predominantly enriched in cardiomyocytes alleviates myocardial metabolic impairment, inflammation, dysfunction, and the risk of mortality caused by lipopolysaccharide and cecal ligation and puncture. Mechanistically, MacroD1 selectively modulates the activity of mitochondrial complex I (MCI), which is particularly vulnerable at the early stages of sepsis. Inhibition of MacroD1 preserves MCI activity and bioenergetic reserves of cardiomyocytes by enhancing mono-ADP-ribosylation of Ndufb9 protein, thereby mitigating sepsis-induced myocardial pyroptosis and dysfunction. These preclinical results indicate that MacroD1 dictates cardiac tolerance to sepsis by configuring MCI-coupled bioenergetic reserve and cardiomyocyte pyroptosis.