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Background Cardiac surgery using cardiopulmonary bypass (CPB) frequently provokes a systemic inflammatory response syndrome, which is triggered by TLR4 (Toll‐like receptor 4) and TNF‐α (tumor necrosis factor α) signaling. Here, we investigated whether the adiponectin receptor 1 and 2 agonist AdipoRon modulates CPB‐induced inflammation and cardiac dysfunction. Methods and Results Rats underwent CPB with deep hypothermic circulatory arrest and were finally weaned from the heart‐lung machine. Compared with vehicle, AdipoRon application attenuated the CPB‐induced impairment of mean arterial pressure following deep hypothermic circulatory arrest. During the weaning and postweaning phases, heart rate and mean arterial pressure in all AdipoRon animals (7 of 7) remained stable, while cardiac rhythm was irretrievably lost in 2 of 7 of the vehicle‐treated animals. The AdipoRon‐mediated improvements of cardiocirculatory parameters were accompanied by increased plasma levels of IL (interleukin) 10 and diminished concentrations of lactate and K+. In myocardial tissue, AdipoRon activated AMP‐activated protein kinase (AMPK) while attenuating CPB‐induced degradation of nuclear factor κB inhibitor α (IκBα), upregulation of TNF‐α, IL‐1β, CCL2 (C‐C chemokine ligand 2), nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, and inducible nitric oxide synthase. Correspondingly, in cultured cardiac myocytes, cardiac fibroblasts, and vascular endothelial cells, AdipoRon activated AMPK, upregulated IL‐10, and attenuated activation of nuclear factor κB, as well as upregulation of TNF‐α, IL‐1β, CCL2, NADPH oxidase, and inducible nitric oxide synthase induced by lipopolysaccharide or TNF‐α. In addition, the treatment of cardiac myocytes with the AMPK activator 5‐aminoimidazole‐4‐carboxamide 1‐β‐D‐ribofuranoside resulted in a similar inhibition of lipopolysaccharide‐ and TNF‐α–induced inflammatory cell phenotypes as for AdipoRon. Conclusions Our observations indicate that AdipoRon attenuates CPB‐induced inflammation and impairment of cardiac function through AMPK‐mediated inhibition of proinflammatory TLR4 and TNF‐α signaling in cardiac cells and upregulation of immunosuppressive IL‐10.