Background: Diabetes is one of the most prevalent metabolic diseases. Irisin (FNDC5 protein) is involved in the new strategy of combating type 2 diabetes. In the liver, the antidiabetic mechanism of silymarin at the molecular level is unknown. This study investigated the effects of silymarin on irisin and the related gene expression and oxidative stress status in the liver of type 2 diabetic rats.Methods: Thirty-six rats were divided into 6 groups (n=6 each) by simple randomization: control, control+silymarin (60 mg/kg daily in normal saline orally for 60 days), control+silymarin (120 mg/kg daily in normal saline orally for 60 days), diabetic, diabetic+silymarin (60 mg/kg daily for 60 days), and diabetic+silymarin (120 mg/kg daily for 60 days). Biochemical parameters were measured by spectrophotometric and immunoassay methods, and quantitative polymerase chain reaction was used to evaluate gene expression. The data were analyzed by one-way ANOVA, followed by the Tukey test, using SPSS software, version 16.0. The results were considered statistically significant at a P value less than 0.05. Results: In the diabetic rats treated with silymarin (60 and 120 mg/kg), by comparison with the diabetic group, body weight (P=0.04 and P=0.02), insulin (P<0.001), expression of PGC-1α (P=0.04 and P=0.02), expression of FNDC5 (P=0.03 and P=0.01), and concentration of irisin in the liver (P=0.02 and P=0.01) and serum (P<0.001) were significantly increased, whereas the levels of glucose (P<0.001), HOMA-IR (P=0.03 and P=0.01), and liver injury markers (P<0.001) were significantly reduced. Oxidative stress status and histopathological changes were improved in the treated groups. Conclusion: These results suggest that silymarin because of its ability to upregulate irisin and antioxidant effects can be considered an antidiabetic agent.