Cardiac hypertrophy are the major health challenges in the whole world. Ginsenoside Rd is an important component of cell growth and tumorigenesis, but the role and mechanism of ginsenoside Rd in pressure overload induced cardiac dysfunction and remodeling are still not fully illuminated. Here, cardiac hypertrophic remodeling and dysfunction were induced by pressure overload in mice. Myocardial histology was detected by Masson's trichrome staining and hematoxylin-eosin staining (H&E). Western blot was used to detect protein levels of signal mediators. Cardiac function was evaluated by echocardiography, and qPCR analysis was used to detect mRNA expression of hypertrophy and fibrosis markers. Cardiomyocyte size was detected by Wheat germ agglutinin (WGA) staining. Dihydroethidine (DHE) staining was used to detect oxidative stress. We also detected the influence of Ginsenoside Rd on rat neonatal cardiac myocytes (NRCMs) treated by Phenylephrine (PE). Our results showed that Ginsenoside Rd significantly improved pressure overload induced contractile dysfunction, fibrosis, cardiac hypertrophy, inflammation and oxidative stress in mice. Moreover, protein levels of AKT, calcineurin A, ERK1/2 and TGF-β1 were significantly decreased in the Ginsenoside Rd-treated hearts as compared to control. Ginsenoside Rd treated in cardiomyocytes inhibited PE-induced cardiomyocyte hypertrophy. These results revealed that ginsenoside Rd improved cardiac dysfunction and remodeling induced by pressure overload, which is related to the inhibition of a variety of signaling pathways.