Chronic liver disease is characterized by an exacerbated accumulation of deposition of collagen, causing progressive fibrosis, which may lead to cirrhosis. We evaluated the inhibitory effect of tetrahydrocurcumin (THC), a major metabolite of curcumin, on liver fibrogenesis both in vitro, HSC-T6 cell, and in vivo, dimethylnitrosamine (DMN)-induced liver fibrosis in rat. The liver inflammation in HSC-T6 cell was initiated by transforming growth factor-β1 (TGF-β1), and fibrosis in Sprague–Dawley rats was induced by intraperitoneal (i.p.) injection of DMN (10mg/kg) 3days per week for four consecutive weeks. THC (10mg/kg) was administered in rats by oral gavage daily. DMN caused hepatic injury as indicated by analysis of liver function, morphology, histochemistry, and fibrotic parameters. Once-daily dosing with THC alleviated liver damage as signified by histopathological examination of the α-smooth muscle actin (α-SMA) and collagen I, accompanied by the reduction TGF-β1 and serum levels of transaminase (P<0.05). These data revealed that the THC exerts hepatoprotective activity in experimental fibrosis, potentially by inhibiting the TGF-β1/Smad signaling.