Repaglinide has the half life of 1 hour, and bioavailability in the body is 56% due to first-pass metabolism. The total daily dose of Repaglinide is 16 mg (e.g., 4 mg four times daily depending on meal patterns); hence, it required frequent dosing. Transdermal patch of Repaglinide was prepared to sustain the release and improve bioavailability of drug and patient compliance. Different formulations were prepared by varying the grades of HPMC and concentration of PVP K30 by solvent casting method. The prepared formulations were evaluated for various parameters like thickness, tensile strength, folding endurance, % elongation, % moisture content, % moisture uptake, % drug content, in vitro drug release, in vitro permeation, and drug excipient compatibility. A 32 full factorial design was applied to check the effect of varying the grades of HPMC (X 1) and PVP concentration (X 2) on the responses, that is, tensile strength, percentage drug released in 1 hr (Q 1), 9 hr (Q 9), and diffusion coefficient as a dependent variables. In vitro release data were fitted to various models to ascertain kinetic of drug release. Regression analysis and analysis of variance were performed for dependent variables. The results of the F2 statistics between factorial design batches and theoretical profile were used to select optimized batch. Batch F6 was considered optimum batch which contained HPMC K100 and PVP (1.5%), showed release 92.343% up to 12 hr, and was more similar to the theoretical predicted dissolution profile (f 2 = 69.187).