Ginsenoside Re, an herbal ingredient from ginseng, has been demonstrated to protect the heart from various cardiovascular diseases. In this study, we investigated the protective effects and mechanisms of ginsenoside Re (Gin-Re) on cardiac function and left ventricular remodeling in a rat model of myocardial infarction (MI). After ligating the left anterior descending coronary artery, Wistar rats were treated with Gin-Re (135 mg/kg) by gavage everyday for 4 weeks. Serological detection showed that Gin-Re significantly inhibited myocardial injury and attenuated oxidative stress in MI rats. Echocardiographic observation showed that Gin-Re significantly improved cardiac function and prevented left ventricular dilatation induced by MI. Pathological observation found that Gin-Re significantly decreased interstitial fibrosis in the left ventricle of MI rats. Compared with the MI group, Gin-Re treatment promoted AMPK alpha phosphorylation, decreased TGF-beta 1 expression, and attenuated Smad2/3 activation. After Gin-Re treatment, the phosphorylation of FAK, PI3K p110 alpha, and Akt was enhanced in MI rats, while PI3K p110 beta showed no difference compared with the MI group. These results indicate that Gin-Re may improve MI-induced cardiac dysfunction and mitigate ventricular remodeling through regulation of the AMPK/TGF-beta 1/Smad2/3 and FAK/PI3K p110 alpha/Akt signaling pathways.