Cardiac fibroblasts play a key role in the process of myocardial remodeling and myocardial fibrosis, which will eventually lead to heart failure. Quercetin Dihydrate has been studied in cardiovascular disease, but its effect on myocardial fibrosis is not clear. Here, cardiac remodeling was induced by infusion of Ang II (1000 ng/kg/min) for 2 weeks in mice. Quercetin Dihydrate was injected intraperitoneally for 25 mM/kg body weight (BW) once two days. We found that Quercetin Dihydrate significantly reduced cardiac contractile function, fibrosis, inflammation and myocardial hypertrophy induced by Ang II. Quercetin Dihydrate could inhibit the expression of Collagen I and Collagen III, which are the markers of fibroblast differentiation. We also verified the inhibitory effect of Quercetin Dihydrate on the proliferation and differentiation of fibroblasts induced by angiotensin II in vitro. Our results show that quercetin dihydrate plays a key role in the progression of myocardial fibrosis and suggests that Quercetin Dihydrate may be a promising drug for the treatment of myocardial fibrosis.