Aim: the aim of this study was to compare the impact of silymarin on the liver fibrosis induced by diethylnitrosamine (DEN) between both sexes of Wistar  rats and proposing possible mechanisms. Main Methods: twenty-four Wistar male and twenty-four Wistar female rats  were randomly assigned into 8 groups according to their sex (n=6) for administration of vehicle, DEN, silymarin or both DEN and silymarin for 8 weeks. At the end of the experiment, the traditional rat body and liver weight parameters, liver injury biomarkers (serum ALT, AST, ALP, and total bilirubin) were measured. Furthermore, hematological parameters, lipid profiles (TC, LDL-C, HDL-C, and TG) and oxidative stress biomarkers (TBARS, SOD, CAT, and GSH) were determined. Also, the inflammatory biomarkers in liver tissue homogenate (TNF-α, TGF-β) were evaluated. Histopathological subjective scoring system graded the damage markers of liver tissue. Expression of NF-kB was measured immunohistochemically. Results: Markedly diminished DEN induced liver fibrosis markers in female groups while worsened in male groups. Silymarin regimen improved liver functions and fibrosis markers. Additionally, it counteracted DEN-induced oxidative stress, lipid peroxidation and inflammations, silymarin provided these ameliorative effects either in males or females rats. Conclusion: Silymarin plays an ameliorative role of DEN-induced liver fibrosis in male and female rats via reducing oxidative stress and inflammations.