The current work aims to study the nephroprotective potential of naringin (NG), a flavanone derived from citrus fruits, in methotrexate (MTX)-induced renal toxicity. Thirty male rats were divided into five groups; control group (IP saline), MTX group (IP single dose, 20 mg/kg), and three groups co-treated with MTX and naringin (IP daily dose; 20, 40, and 80 mg/kg, respectively). Kidney tissues were used to investigate renal function, oxidative stress, lipid peroxidation, and caspase-3 activity. Biochemical cytokine analysis was performed in addition to ultrastructural examinations of kidney tissue. When compared to the MTX-treated rats, MTX+NG significantly reduced the levels of urea, creatinine, MDA, NO, TNFα, IL-6, and caspase-3 activity. A significant increase in the levels of the antioxidant enzymes and GSH were also noted. Additionally, naringin ameliorated the apparent ultrastructural changes observed in the glomeruli and renal tubules of MTX-intoxicated rats. Noticeable structural improvements of glomerular lesions, proximal, and distal convoluted tubular epithelium were observed in MTX+NG treated animals, including podocytes with regular foot processes, perfectly organized filtration barrier, no signs of GBM thickening, organized brush border, and normal architecture of microvilli. Naringin (80 mg/kg) had the maximum amelioration effect. To the best of our knowledge, this is the first study to investigate the ultrastructural manifestations of naringin and/or MTX on the kidney of rats. Taken all, naringin has a potent therapeutic effect and can be used in adjuvant therapy to prevent MTX-induced nephrotoxicity. Nevertheless, the molecular mechanism underlying the nephroprotective capacity of naringin needs further investigation.