Background: The loss of kidney function caused by persistent diabetes mellitus is known as diabetic nephropathy (DN). The primary goal of research on diabetes is to restore the normoglycemic condition. A synthetic medicine called metformin, a guanidine derivative, has a clinical role in the management of people with type 2 diabetes. To address type 2 diabetes mellitus, nano emulsion drug delivery devices are now thought to be an effective alternative option. The study's goal is to evaluate the potential ability of metformin and metformin nano emulsion in the treatment of Streptozotocin (STZ)-induced diabetes in rats. Materials & methods: 40 male albino rats were categorized into four groups: Control negative group I; Diabetic group II (administered a single intra-peritoneally (IP) injected dose of 60 mg/kg STZ); Metformin treated (STZ& MET) group III (treated with daily oral dosage of metformin 18 mg/kg) and Nano-metformin (STZ& Nano-MET) group IV (received daily oral dosage of metformin nano-emulsion 18 mg/kg) for 4 weeks. Eight weeks later, animals were sacrificed, histopathological and immunohistochemical assays were performed. Results: diabetic group exhibited vacuolated, hemorrhagic, and enlarged glomerular bed, increased Bowman's filtration spaces, vacuolating degeneration and obliterated convoluted tubules, necrotic changes, hemorrhagic areas, and infiltration of inflammatory cells. Besides, fibrosis, thickening in basement membrane and amyloid deposits was observed among renal tissue. While metformin treated group showed slight improvement including decrease of amyloid deposits and less collagen fibers with moderate Bcl-2 reaction among induced diabetic group and Nano-MET treated group showed high efficiency in the improvement of diabetic renal pathological changes including normal renal histoarchitecture, absence of amyloid deposits and scanty collagen fibers with severe Bcl-2 reaction. Conclusion: In DN animal model, our data highlighted the high efficiency of nano-metformin in improving inflammation, fibrosis, and apoptosis more than the regular metformin group.