The current work attempted to evaluate a nanoemulsion approach that improved percutaneous glimepiride absorption. Nanoemulsions do not require chemical enhancers and have several advantages over traditional transdermal drug delivery techniques. Pseudoternary phase diagrams were created to optimize the surfactant, cosurfactant, and surfactant : cosurfactant weight ratios (Smix). The nanoemulsion formulation comprises Labrafac and Triacetin (1:1 ratio) as an internal oil phase in an external aqueous phase, Tween 80 as a surfactant, and diethylene glycol monoethyl ether as a cosurfactant. A pseudoternary phase diagram was developed to investigate the effect of the surfactant to cosurfactant mass ratio (Smix) on nanoemulsion production, which is a transparent zone. Nine nanoemulsion formulations were chosen and characterized. The nanoemulsion formulations exhibited small droplet size, homogenous size distribution, and low viscosity. The study found that the nanoemulsion gel for transdermal systems of Glibenclamide had superior management of hyperglycaemia and alleviated diabetes mellitus problems than oral Glibenclamide treatment in wistar rats. Transdermal nanoemulsion formulations demonstrated superior enhancement in all biochemical assays compared to oral treatment. They improved tissue healing following diabetes-induced tissue damage. A novel glimepiride nanoemulsion formulation could be developed and projected to be suited for transdermal use.c