Restoration of the normoglycemic state is the basic tenet of diabetes research. Nowadays, using nanoemulsion drug delivery systems represent an alternative effective tool in Type 2 diabetes mellitus management. We aimed to investigate the anti-diabetic potential of metformin nanoemulsion and mesenchymal stem cells (MSCs) therapy on streptozotocin (STZ)-induced diabetic rat model. Nanoemulsion formulation was prepared with oil phase (5%v/v), 1gm metformin with a hydrophilic surfactant, then characterized for particle size and zeta potential.Adult male albino rats were induced for diabetes with 60 mg/kg STZ and were classified into 4 groups: STZ control group; STZ+MET group (orally administered daily dose of metformin 18 mg/200 g b.wt.); STZ+MSCs group (mono-therapeutic dose of BM-MSCs 1×10⁶ cells/rat) and STZ+Nano-MET group (daily intraperitoneal dose of metformin nanoemulsion 18 mg/kg b.wt.). After 8 weeks, relative expression levels of hepatic IRS-1, AKT, Bcl-2, and Bax were assessed by qPCR. Also, histopathological investigations were performed. We reported cytoplasmic vacuolation, tissue necrosis, dilated blood sinusoid and congested hepatic vein in STZ group. Experimental animals either treated with metformin nanoemulsion or the mono-therapeutic dose of MSCs exhibited significant up-regulation in IRS-1/AKT pathway and Bcl-2 gene expression levels, as well as significant repression in Bax mRNA levels, besides a remarkable amelioration in a hepatic histological organization.Conclusion: Nano-MET holds an anti-diabetic potential that clearly surpasses metformin via affecting the insulin signaling pathway and apoptotic gene expression.