Abstract: Background and Objective: There is a widespread use of medicinal herbs with beneficial uses against different diseased conditions. This study was carried out to identify and study the biological effect of Acacia gerrardii leaf extract on lowering blood sugar in rats suffering from diabetic nephropathy. Materials and Methods: It studied the effects of leaf extract at concentrations ranging from 100-500 mg kg–1 b.wt. per day for 4 weeks. Serum glucose levels, total lipids profile and kidney functions were estimated. Plasma levels of sodium and potassium as well as total bilirubin levels were assessed and kidneys from different groups were histopathologically examined. Results: The results showed that leaves were rich in the major compounds of phenolic acids, including salicylic acid and flavonoids with reduction of total lipids, triglycerides and total cholesterol in diabetic rats with renal failure together with reduction in uric acid, creatinine and urea with reduced vacuolar degeneration of tubules and basement membrane thickening. Additionally, the phylogenetic analysis using ISSR primers detected a genetic divergence among different samples. The results showed that the rich antioxidant content of Acacia gerrardii improved lipid, serum antioxidant and kidney function profiles in diabetic rats. Conclusion: Acacia gerrardii could be used as a safe source of antioxidants. Moreover, the ISSR assay proved its usefulness in detecting genetic variations among different Acacia gerrardii samples.