Objective To investigate the inhibitory effect of Sauchinone (Sch) on renal tissue fibrosis and its mechanism in unilateral ureteral obstruction (UUO) mice. Methods Forty male ICR mice were taken and divided into sham-operated group (Sham group), UUO fibrosis model group (UUO-Model group), Sch low-dose group (Sch-Low group), Sch high-dose group (Sch-High group), and valsartan-positive control group (Val group). Starting on day 2 after surgery, the Sch low-dose group (10 mg/kg), the Sch high-dose group (30 mg/kg), and the valsartan-positive control group (100 mg/kg) were administered by gavage once daily for 4 weeks, respectively. At the end of drug administration, serum levels of creatinine (SCr), blood urea nitrogen (BUN), and inflammatory factors TNF-α and IL-6 were measured; SOD activity, MDA and ROS content were detected in renal tissues; the levels of inflammatory factors TNF-α and IL-6 mRNA were detected in renal tissues by RT-qPCR; HE, Masson staining, and immunohistochemistry were used to detect pathological changes and collagen deposition as well as TGF-β1, Smad3, and CTGF protein expression in mouse renal tissues; Western blot method was used to observe Collagen Ⅰ, CTGF, Smad3, Nrf2, HO-1 and NF-κB protein expression in renal tissues. Results Compared with the UUO model group, the serum levels of SCr and BUN as well as TNF-α and IL-6 were significantly reduced in the Sch low-dose and Sch high-dose groups of mice (P<0.05 or P<0.01); SOD activity was significantly higher and MDA and ROS levels were significantly lower in renal tissues (P<0.05 or P<0.01); The expression of TNF-α and IL-6 mRNA in renal tissues was significantly reduced (P<0.05 or P<0.01); Microscopic observation of swollen renal tubules with thylakoid hyperplasia and collagen fiber deposition was significantly improved; Immunohistochemistry showed a significant reduction in TGF-β1, Smad3 and CTGF protein expression in renal tissues; Western blot showed that Collagen Ⅰ, CTGF, Smad3, NF-κB protein expression was significantly reduced (P<0.05 or P<0.01); meanwhile, Nrf2, HO-1 protein expression was significantly elevated (P<0.05 or P<0.01). Conclusion The mechanism of the amelioration of renal tissue fibrosis by triphalaenone may be mediated through anti-inflammatory, anti-oxidative stress effects that modulate the expression of pro-fibrotic proteins of the TGF-β1/Smad3 signaling pathway.