Transdermal drug delivery has been widely adopted as a plausible alternative to the oral route of administration, especially for drugs with poor systemic bioavailability. The objective of this study was to design and validate a nanoemulsion (NE) system for transdermal administration of the oral hypoglycemic drug glimepiride (GM). The NEs were prepared using peppermint/bergamot oils as the oil phase and tween 80/transcutol P as the surfactant/co-surfactant mixture (Smix). The formulations were characterized using various parameters such as globule size, zeta potential, surface morphology, in vitro drug release, drug-excipient compatibility studies, and thermodynamic stability. The optimized NE formulation was then incorporated into different gel bases and examined for gel strength, pH, viscosity, and spreadability. The selected drug-loaded nanoemulgel formulation was then screened for ex vivo permeation, skin irritation, and in vivo pharmacokinetics. Characterization studies revealed the spherical shape of NE droplets with an average size of ~80 nm and a zeta potential of −11.8 mV, which indicated good electrokinetic stability of NE. In vitro release studies revealed enhanced drug release from the NE formulation compared to the plain drug. GM-loaded nanoemulgel showed a 7-fold increment in drug transdermal flux compared to plain drug gel. In addition, the GM-loaded nanoemulgel formulation did not elicit any signs of inflammation and/or irritation on the applied skin, suggesting its safety. Most importantly, the in vivo pharmacokinetic study emphasized the potential of nanoemulgel formulation to potentiate the systemic bioavailability of GM, as manifested by a 10-fold rise in the relative bioavailability compared to control gel. Collectively, transdermal NE-based GM gel might represent a promising alternative to oral therapy in the management of diabetes.