Pirfenidone (PFD) is a novel anti-fibrotic agent that targets TGF beta. However, the mechanisms underlying its renoprotective properties in hypertension-induced renal injury are poorly understood. We investigated the renoprotective properties of PFD and clarified its renoprotective mechanisms in a rat hypertension-induced renal injury model. Dahl salt-sensitive rats were fed a high-salt diet with or without 1% PFD for 6 weeks. During the administration period, we examined the effects of PFD on blood pressure and renal function. After the administration, the protein levels of renal TGF beta, Smad2/3, TNF alpha, MMP9, TIMP1, and catalase were examined. In addition, total serum antioxidant activity was measured. Compared to untreated rats, PFD treatment significantly attenuated blood pressure and proteinuria. Histological study showed that PFD treatment improved renal fibrosis. PFD may exert its anti-fibrotic effects via the downregulation of TGF beta-Smad2/3 signaling, improvement of MMP9/TIMP1 balance, and suppression of fibroblast proliferation. PFD treatment also increased catalase expression and total serum antioxidant activity. In contrast, PFD treatment did not affect the expression of TNF alpha protein, macrophage or T-cell infiltration, or plasma interleukin 1 beta levels. PFD prevents renal injury via its anti-fibrotic and anti-oxidative stress mechanisms. Clarifying the renoprotective mechanisms of PFD will help improve treatment for chronic renal diseases.