Cardiac remodeling and subsequent heart failure is an increasing public health problem after myocardial infarction (MI). The aim of our research is to investigate whether gene therapy of growth hormone secretagogue receptor 1a may regulate cardiac remodeling and function after MI. Adenoviral vector expressing GHSR-1a or empty adeno-null was injected into rat peri-infarct myocardium after left anterior descending coronary artery ligation. GHSR-1a expression was confirmed by western blotting. 14 days after operation, haemodynamic and echocardiographic analysis demonstrated that GHSR-1a treatment significantly improved survive rate, increased scar thickness, preserved LV diameter, restored cardiac function and increased angiogenesis. There was no difference in infarct size between MI+Ad-GHSR-1a group and MI + Ad-null group. Additionally, increased protein expression of Akt phosphorylation and AMP-activated protein kinase phosphorylation in the infarct border myocardium were also observed. Moreover, GHSR-1a overexpression significantly enhanced tube formation in human umbilical endothelial cells (HUVECs) under ischemia condition. Knockdown of GHSR-1a by siRNA markedly decreased vascular endothelial growth factor expression as well as mRNA levels of Akt and AMPK. In conclusion, GHSR-1a gene therapy improves cardiac remodeling and function in rats after myocardial infarction. This may be a new anti-remodeling target to MI.