Purpose <p>Diabetic nephropathy (DN), complication of diabetes, is caused by persistent hyperglycemia leading to oxidative stress and inflammation in renal tissues. Carvacrol, natural phenolic compound, shows protective effects but has issues with solubility and bioavailability. The current study aimed to prepare and characterize carvacrol loaded cubosomes to improve delivery and therapeutic efficacy on HFD-STZ induced diabetic nephropathy in rats.</p> Methods <p>Carvacrol- loaded cubosomes were prepared and optimized using Box-Behnken Design and compatibility of the drugs and the excipients were established by using various analytical techniques. The optimized formulation (Batch F16) exhibited an entrapment efficiency of 92%, nano-sized particles (265.1&#xa0;nm), a polydispersity index of 0.281, and a stable zeta potential of -16.7 mV was selected for Ex-vivo (intestinal permeability) and In vivo (HFD-STZ induced diabetes in rats) studies.</p> Result <p>Ex-vivo permeability showed greater intestinal absorption of carvacrol- loaded cubosomes as compared to carvacrol. In vivo, carvacrol- loaded cubosomes substantially improved body weight, glucose levels, lipid profile and renal function markers such as BUN, creatinine, albumin and urine albumin, creatinine. Carvacrol cubosomes raised levels of antioxidants and lowered lipid peroxidation and TNF- α in kidney homogenates. Molecular docking results were also supported a high affinity of carvacrol toward some important proteins related to glucose metabolism, lipid metabolism and oxidative stress.</p> Conclusion <p>The results indicated that carvacrol- loaded cubosomes possessed strong nephroprotective, antioxidant, and anti-inflammatory effects than plain carvacrol and therefore, can act as a new therapy in the treatment of diabetic nephropathy.</p>