Abstract Background and purpose: Methotrexate as a chemotherapy drug causes chronic liver damage, infiltration of neutrophils, oxidative stress, and direct renal tubular damage. Quercetin is a flavonoid with antioxidant and anti-inflammatory properties. Therefore, the aim of this study was to investigate the effect of quercetin on eliminating the liver and kidney toxicity of methotrexate. Materials and methods: In this experimental study, 32 rats were divided into 4 groups. Group I (control) was given regular diet. Group II received single-dose methotrexate. Group III received methotrexate + a single dose quercetin and the last group (positive control) received methotrexate + a single dose silymarin. After five days, blood samples were taken and the serum GOT, GPT, ALP, Cr, urea and antioxidant capacity of plasma were measured. Some parts of liver and kidney were removed to measure the liver and kidney SOD, MDA, catalase activity and histopathological studies. Results: Serum GOT, GPT, ALP, Cr, and liver and kidney MDA were significantly higher (P<0.05) in group II, compared with those of the control group. These parameters significantly decreased (P<0.05) in group III. Compared to the control group, antioxidant capacity of plasma, activity of the liver and kidney SOD, catalase and serum urea decreased significantly in group II (P<0.05). Administration of quercetin significantly increased these parameters (P<0.05) and decreased hepatic and renal lymphocyte infiltration. Conclusion: According to the results, administration of quercetin could have a protective role in preventing liver and renal toxicity induced by methotrexate which could be due to its antioxidant property
