Transdermal drug delivery is an alternative route for systemic drug delivery which minimizes the absorption and increases the bioavailability. Nateglinide is an Anti-Diabetic drug with a shorter half life, low bioavailability up to 72 % undergoes extensive first pass metabolism are required to maintain the therapeutic level it has chosen as transdermal drug delivery system. The present study was to formulate and evaluate transdermal drug delivery system of Nateglinide using polymers such as HPMC & Eudragit RL100 by solvent casting technique. The prepared formulations were evaluated for different physicochemical characteristics like Weight Variation, Folding Endurance, Flatness, pH of patches, % Moisture Content, % Moisture uptake, % Elongation, % Drug Content & % Drug Release. The drug release characteristics of the formulation were studied in-vitro by using semi-permeable membrane. The in-vitro drug release plot has shown that the drug release followed zero order kinetics & Higuchi model, which was evidenced from the regression values. Based on the drug release and physicochemical values obtained from the formulation F 7 is considered as an optimized formulation which shows higher percentage of drug release (96.27±0.68 % at 14 hour) with diffusion mediated mechanism. Korsmeyer-Peppas exponential plots shows fairly linear & it is well supported by their regression coefficients values & slope value (n) were >1 which suggest that drug was released by Super Case-II transport.