Background: Despite high efficacy-to-toxicity ratio of chemotherapeutic agent, methotrexate, toxicity remains a major concern that limits its use. Inflammatory, oxidative stress and fibrotic pathways are implicated in methotrexate-induced injury. This study aims to investigate the ability of losartan to limit methotrexate-induced liver and lung injury and to elucidate the possible underlying mechanisms. Methods: Liver and lung injury was induced in adult male Wistar rats via methotrexate ip injection twice weekly for 4weeks (0.5mg/kg), animals were divided into group1 (control) where rats received saline ip twice weekly with daily vehicles for 4weeks; group 2 to 4 included rats treated with methotrexate and began to receive drugs or vehicles concurrently, where in group2 rats received vehicles daily, whereas in group3 rats received losartan at 10mg/kg/day by gavage and those of group4 received both losartan and bisphenol-A-diglycidyl ether (BADGE, 30mg/kg). Circulating liver enzymes, histological examination of liver and lung as well as peroxisome proliferator-activated receptor-γ (PPAR-γ)/transforming growth factor-β (TGF-β)/SMAD3 and nuclear factor (erythroid-derived2)-like2 (Nrf2)/antioxidants pathways were investigated. Results: Losartan ameliorated methotrexate-induced hepatic and pulmonary injury manifested by improved circulating liver enzymes, restoration of normal liver and lung histology, upregulated PPAR-γ, suppressed TGF-β/SMAD3 signaling while activated Nrf2-mediated antioxidant defenses and reduced lipid peroxidation biomarker malondialdehyde. Losartan effects were abrogated on concurrent use of BADGE, a selective PPAR-γ antagonist. Conclusions: Losartan’s antifibrotic effect via suppression of TGF-β/SMAD3 profibrotic signaling and antioxidant potentials through activation of Nrf2/antioxidant pathway are more likely attributed to PPAR-γ induction. This suggests the usefulness of losartan in limiting methotrexate-associated multiorgan injury.