Metformin reduces glucose level and improves insulin sensitivity. Recently, metformin has gained attention for its pleiotropic effects. In this study, we examined the effect of metformin in a rat model of renal fibrosis. Rats were randomly assigned to one of four groups (n = 6/group): 1, control negative: received saline, 2, control positive UUO: rats underwent 14 days UUO and 3, (Metformin + UUO): rats received oral metformin (300 mg/kg/day daily ×21 days). 4, (Metformin +Captopril + UUO): rats were treated by metformin (300 mg/kg/day daily ×21 days) and Captopril (50 mg/Kg/day ×21 days). UUO induced a significant increase in serum creatinine and serum K⁺ levels. Also, KIM-1 and Wnt/β-catenin expressions are upregulated after UUO. Metformin led to a significant decrease in serum creatinine level and a significant increase in serum irisin level. Metformin administration attenuated UUO -induced increase in MDA and NOX-4 and increased GSH level. Moreover, metformin led to a significant decrease in KIM-1 expression and Wnt/β-catenin expression in renal tissue. Overall, our results suggest a potential protective role of metformin in UUO -induced renal fibrosis via attenuation of expression of NOX-4, KIM-1 and Wnt/β-catenin and increase serum irisin level.