Left ventricular (LV) remodeling, which includes ventricular dilatation and increased interstitial fibrosis after myocardial infarction (MI), is the critical process underlying the progression to heart failure (HF). Therefore, a novel approach for preventing LV remodeling after MI is highly desirable. Yuzu is a citrus plant originating in East Asia, and has a number of cardioprotective ingredients such as hesperidin. However, no study has proved whether yuzu can prevent LV remodeling. The aim of this study was to determine the effects of yuzu on HF and its potential impact on the LV remodeling process after MI and platelet aggregation. In this study, it was investigated whether yuzu and its components hesperidin and naringin, have anti-platelet activities. Yuzu and hesperidin inhibited collagen-, arachidonic acid (AA)-, ADP- and thrombin-induced rat platelet aggregation in vitro and ex vivo. Naringin also inhibited platelet aggregation induced by collagen, AA, or thrombin, but not by ADP. The oral administration of yuzu or hesperidin prolonged mouse tail vein bleeding time in a dose-dependent manner. LV remodeling in vivo study using the permanent left anterior descending coronary artery (LAD) occlusion model demonstrated that one week pretreatment with yuzu or its major metabolite hesperidin before LAD occlusion significantly attenuated cardiac dysfunction, myocyte apoptosis and inflammation. Not only yuzu but also hesperidin inhibited caspase-3 activity, myeloperoxidase expression, α-smooth muscle actin expression, and matrix metalloproteinase-2 activity in a permanent LAD occlusion rat model. These results suggest that yuzu and hesperidin have anti-platelet activity, and that intake of yuzu, which contains various flavonoids such as hesperidin, may be beneficial for individuals at high risk of cardiovascular diseases. These findings provide the first evidence that yuzu and hesperidin prevent MI-induced ventricular dysfunction and structural remodeling of myocardium.