Hsp90 is a molecular chaperone that contributes to the regulation of various cell signaling pathways. In our previous study, we showed that an inhibition of Hsp90 prevented cardiac fibrosis and preserved cardiac function during the development of chronic heart failure (CHF). Simvastatin, an inhibitor of HMG-CoA reductase, has been shown to inhibit the chaperone activity of Hsp90. However, it is unclear whether simvastatin can prevent myocardial fibrosis by inhibiting Hsp90. Therefore, we examined effects of simvastatin in the models of CHF. The results showed that treatment with simvastatin prevented cardiac fibrosis. Furthermore, simvastatin treatment inhibited the c-Raf-Erk1/2 pathway, which contributes to cardiac fibrosis. In vitro experiment, the interaction of Hsp90 with c-Raf in cultured cardiac fibroblasts was decreased by the presence of simvastatin, and the expression level of c-Raf was also reduced. Furthermore, simvastatin inhibited the fibroblast proliferation and migration. Simvastatin also attenuated collagen production by inhibiting the differentiation of cardiac fibroblasts into myofibroblasts. These results suggest that an inhibition of Hsp90 is partially responsible for the inhibitory effect of simvastatin on cardiac fibrosis.