In chronic kidney disease (CKD), hyperuricemia is a common phenomenon, presumably due to reduced renal clearance of uric acid. This study investigated the effect of xanthine oxidase (XO) inhibitors allopurinol and febuxostat to prevent oxidative stress in the kidney of two-kidney, one-clip (2K1C) rats. In this investigation, 2K1C rats were used as an experimental animal model for kidney dysfunction. 2K1C rats were provided with food and drinking water and received febuxostat at a dose of 10 mg/kg or allopurinol at 100 mg/kg, respectively. After the treatment completion, all rats were sacrificed, and tissue samples were collected. 2K1C rats exhibited increased plasma creatinine, uric acid level, and glomerular injury assessed based on microscopic findings. Both allopurinol and febuxostat significantly normalized creatinine and uric acid levels. Furthermore, 2K1C rats showed increased lipid peroxidation (LPO), nitric oxide (NO), and advanced oxidation protein products (AOPP) alongside decreased superoxide dismutase (SOD) and catalase activity. Again, both drug treatments ameliorated these elevated oxidative stress parameters in 2K1C rats. The antioxidant genes such as Nrf-2, HO-1, and SOD were also restored in the kidneys of 2K1C rats by allopurinol and febuxostat treatment. 2K1C rats also showed increased IL-1β, IL-6, TNF-α, and NF-кB mRNA expression in the kidneys which were normalized by allopurinol and febuxostat treatment. Thus, the data suggest that XO inhibition protects kidney function potentially by restoring antioxidant enzyme function and suppressing inflammation.