The renoprotective potential of nanoemulsified garlic oil blend (GNE) in alleviating the progressive stages of hyperlipidemia-mediated diabetic nephropathy was examined. The study was carried out in high fat-fed, streptozotocin-induced type 2 diabetic Wistar rats for five months. The diabetic rats showed a significant increase of area under the curve in OGTT (p < 0.01) and IPITT (p < 0.01), increased urinary albumin (p < 0.01), urinary microprotein (p < 0.001), total cholesterol (p < 0.01), triglycerides (p < 0.001) and LDL cholesterol (p < 0.001), with decreased serum albumin (p < 0.01), serum protein (p < 0.001) and HDL-cholesterol levels (p < 0.05) than the control rats. The histopathological analysis evidenced mesangial expansion and hypercellularity at the end of the first and third month, and glomerulosclerosis and tubular atrophy at the end of the fifth month in diabetic rats. Moreover, on disease progression, increase in urinary podocalyxin, NGAL and CD36 was observed, and the renal mRNA and protein expression of podocalyxin decreased significantly with a concomitant increase in NGAL and CD36 expression from first till fifth month end. The treatment with GNE (20 mg/kg) significantly ameliorated the serum albumin (p < 0.001) and urine albumin (p < 0.01) from the end of the third month with significant attenuation in the lipid profile than GO (20 mg/kg) or Ator (8 mg/kg). Moreover, GNE reverted the histopathological alterations and attenuated the aberrant mRNA, protein expression and urinary excretion level of renal CD36, podocalyxin and NGAL in diabetic rats from an early stage of disease till the end of the study period. This study demonstrated the enhanced efficacy of GO in nanoemulsified form in mitigating the progression of nephropathy in type 2 diabetic rats. © 2020, King Abdulaziz City for Science and Technology.