Objectives This study was designed to investigate the effect of Morus nigra fruit extract in retarding the progression of diabetic nephropathy in streptozotocin (STZ)-induced diabetic rats. Methods Diabetic male Wistar rats were injected with black mulberry fruit extract (BMFE) at doses of 150 and 300 mg/kg body weight. After 4 weeks, microalbuminuria was estimated in addition to serum concentrations of glucose, insulin, creatinine and albumin. Key findings The study revealed a significant amelioration of all the measured parameters in diabetic animals. In addition, MDA, lipid peroxide levels and catalase activity were also improved. The histopathological examination of kidney tissues revealed significant improvement of the pathological changes and glomerular sclerosis in diabetic rats treated with BMFE. Treated rats showed downregulation of TNF-α, vascular cell adhesion molecule-1 (VCAM-1) and fibronectin mRNA expression. Conclusion The ameliorative effect of BMFE on diabetic nephropathy is not only through its potent antioxidant and hypoglycaemic effects but also through its downregulation of TNF-α, VCAM-1 and fibronectin mRNA expression in renal tissues of diabetic-treated rats. Therefore, BMFE as dietary supplement could be a promising agent in improving diabetic nephropathy. Methods Chemicals Authentic anthocyanin samples of cyanidin-3-O-glucoside and cyanidin-3-O-rutinoside for high-performance liquid chromatography (HPLC) analysis were purchased from Phytoplan company (Germany). Streptozotocin (STZ), chloroform and isopropanol were obtained from Sigma-Aldrich (St. Louis, MO, USA). Authentic samples for HPLC analysis of flavonoids rutin, quercetin, quercetrin, catechin, kaemferol, naringin and phenolic acids chlorogenic, gallic, caffeic, ellagic and cinnamic acids were purchased from Sigma-Aldrich, Germany and were kindly supplied by Food Technology Research Institute, Giza, Egypt. TRizol was obtained from Genetix Branid Co. (Genetix Biotech Asia Pvt. Ltd., New Delhi, India). QuantiFast SYBR Green PCR Master Mix unit was provided by QIAGEN (Hilden, Germany). HiSenScript TM [-] cDNA synthesis kit was purchased from iNtRON Biotechnology Company. The other reagents were of analytical, high-performance liquid chromatography (HPLC), or the best accessible pharmaceutical grades.