Endogenous ghrelin and its synthetic mimetics are peptide growth hormone (GH) secretagogues (GHSs) that exert a variety of cardioprotective effects. There are experimental evidence suggesting the beneficial effects of GHSs on ischemia/ reperfusion (I/R) injury, myocardial infarction (MI), heart failure (HF), isoproterenol-induced injury, and doxorubicin-induced cardiotoxicity. The effects of GHS were mediated by improving contractility and cardiac output, vasodilation, boosting cardiac antioxidant potential, reducing infarct size, and inhibition of cardiac apoptosis and fibrosis. The existing literatures have confirmed the improvement of cardiac function, attenuation of inflammation, rebalancing the autonomic nervous system (ANS), suppression of cardiac remodeling, improving arrhythmia and HF by GHS in experimental animal models and clinical patients. However, the molecular mechanisms of GHS on HF have not been fully elucidated. Here, we summarize available recent data on improving HF by GHS through molecular signaling pathways, to propose a novel strategy for the prevention and treatment of HF.