Background: Recently, the development of cardiovascular disease (CVD) has been proved to be closely associated with depression in which 5-HT plays a crucial role. Ginseng Fruit Saponin (GFS) and Metoprolol are two drugs which have beneficial effects on the cardiovascular system in Myocardial Infarction (MI) mice. However, their effects on depression-like behaviors after MI and its underlying mechanisms remain unknown. We aimed to investigate their antidepressive-like effects as well as their impacts on the 5-HT system. Methods: The MI model was established by ligating left anterior descending coronary artery. Mice were administered with GFS, Metoprolol or saline for 4 weeks. Cardiac function was evaluated and depressive-like behaviors were quantified at the end of the experiments. Masson's staining was used to assess myocardial fibrosis while immunohistochemistry, western blot, ELISA and qPCR were performed to analyze the levels of 5-HT and its related genes. Results: Compared with MI groups, Both GFS and Metoprolol treatments significantly improved cardiac function and reduced myocardial fibrosis. Moreover, GFS but not Metoprolol increased the levels of 5-HT in the cortex and rescued depression-like behaviors in MI mice. Conclusions: GFS has potential antidepressive effects and the mechanisms involve the regulation of 5-HT concentrations in the cortex.