Cardiac fibrosis critically injured the cardiac structure and function of the hypertensive patients. However, the anti-fibrotic strategy is still far from satisfaction. This study aims to determine the effect and mechanism of Pirfenidone (PFD), an anti-lung fibrosis medicine, in the treatment of cardiac fibrosis and heart failure induced by pressure overload. Male C57BL/6 mice were subjected to thoracic aorta constriction (TAC) or sham surgery with the vehicle, PFD (300 mg/kg/day) or Captopril (CAP, 20mg/kg/day). After 8 weeks of surgery, mice were tested by echocardiography, and then sacrificed followed by morphological and molecular biological analysis. Compared to the sham mice, TAC mice showed a remarkable cardiac hypertrophy, interstitial and perivascular fibrosis and resultant heart failure, which were reversed by PFD and CAP significantly. The enhanced cardiac expression of TGF-beta 1 and phosphorylation of Smad3 in TAC mice were both restrained by PFD. Cardiac fibroblasts isolated from adult C57BL/6 mice were treated by Angiotensin II, which led to significant increases in cellular proliferation and levels of alpha-SMA, vimentin, TGF-beta 1 and phosphorylated TGF-beta 1 receptor and Smad3. These changes were markedly inhibited by pre-treatment of PFD. Collectively, PFD attenuates myocardial fibrosis and dysfunction induced by pressure overload via inhibiting the activation of TGF-beta 1/Smad3 signalling pathway.