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Visual Abstract, Highlights • Systemic treatment of an antibody-based glucagon receptor antagonist confers cardioprotection against myocardial infarction and post-myocardial infarction remodeling in mice. • Systemic treatment of glucagon receptor antagonist prevents pressure overload induced cardiac remodeling and dysfunction in mice. • Glucagon receptor antagonist treatment attenuates the pathological progression of heart failure induced by pressure overload in mice. • Long-term suppression of glucagon signaling is potentially an effective therapy for heart failure with different etiologies independent of metabolic disorders., Summary Mice were treated with a fully human monoclonal glucagon receptor antagonistic antibody REMD2.59 following myocardial infarction or pressure overload. REMD2.59 treatment blunted cardiac hypertrophy and fibrotic remodeling, and attenuated contractile dysfunction at 4 weeks after myocardial infarction. In addition, REMD2.59 treatment at the onset of pressure overload significantly suppressed cardiac hypertrophy and chamber dilation with marked preservation of cardiac systolic and diastolic function. Initiation of REMD2.59 treatment 2 weeks after pressure overload significantly blunted the progression of cardiac pathology. These results provide the first in vivo proof-of-concept evidence that glucagon receptor antagonism is a potentially efficacious therapy to ameliorate both onset and progression of heart failure.