Objective To investigate the inhibitory effect of Sauchinone (Sch) on renal tissue fibrosis and to explore its mechanism in unilateral ureteral obstruction (UUO) mice. Methods Forty male ICR mice were divided into Sham, UUO-Model, Sch Low-dose, Sch High-dose, and positive control (Val) groups. Mice in the sham group underwent isolation of the left renal ureter without ligation, and mice in the UUO-Model group underwent stripping of the left proximal ureter for double ligation. Starting on day 2 after surgery, the Sch Low-dose group received 10 mg/kg Sch, the Sch High dose group received 30 mg/kg Sch, and the Val group received 100 mg/kg valsartan by gavage once daily for 4 weeks. At the end of drug administration, serum creatinine (SCr), blood urea nitrogen (BUN), and the inflammatory factors tumor necrosis factor (TNF)-α and interleukin (IL)-6 were measured. Superoxide dismutase (SOD) activity, and malondialdehyde (MDA) and reactive oxygen species (ROS) content were detected in renal tissues. TNF-α and IL-6 mRNA levels were detected in renal tissues by reverse transcription-quantitative polymerase chain reaction. Pathological changes and collagen deposition, as well as transforming growth factor (TGF)-β1, Smad3, and connective tissue growth factor (CTGF) protein expression in mouse renal tissues were detected by hematoxylin and eosin and Masson staining, and immunohistochemistry. Collagen Ⅰ, CTGF, Smad3, nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and nuclear factor (NF)-κB protein expression in renal tissues were detected by Western Blot. Results SCr, BUN, TNF-α, and IL-6 were all significantly reduced in Sch Low-dose and Sch High-dose mice compared with the UUO Model group (P<0.05 or P<0.01), while SOD activity was significantly higher and MDA and ROS levels were significantly lower in renal tissues (P<0.05 or P<0.01), and TNF-α and IL-6 mRNA in renal tissues were 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, and Western Blot showed significantly reduced levels of Collagen Ⅰ, CTGF, Smad3, and NF-κB protein expression (P<0.05 or P<0.01), while Nrf2 and HO-1 protein expression levels were significantly elevated (P<0.05 or P<0.01). Conclusions The amelioration of renal tissue fibrosis by sauchinone may be mediated via anti-inflammatory and antioxidative stress effects that modulate the expression of pro-fibrotic proteins in the TGF-β1/Smad3 signaling pathway.