Transdermal drug delivery is an alternative route for systemic drug delivery which increases bioavailability and minimizes absorption. Orally ketoconazole (KTC) causes serious liver injury, increases dosing frequency, undergoes first pass hepatic and gastrointestinal metabolism. The purpose of this research work was to formulate and evaluate the matrix type of transdermal drug delivery system of ketoconazole. KTC patches were developed by using polymers HPMC (E15LV), Eudragit-L-100, PVP, Eudragit-S-100 by employing solvent casting method and reducing toxic effects. Oleic acid and Tween 80 were selected as permeation enhancer and PEG400 as plasticizer. F1-F9 formulations were prepared and evaluatedfor physicochemical characteristics (Thickness, flatness, uniformity of weight, moisture content, moisture loss, swelling index, folding endurance), drug content and in-vitro drug release studies. Based on the drug release and physicochemical values obtained, the formulation KTC4 showed a high percentage of drug release of 97.1% in 12 hr and was considered as an optimized formulation. FTIR and DSC studies indicated that there was no interaction between drug and excipients. From the present study it was concluded that KTC4 formulation followed zero order mechanism of drug release, promoting controlled release of the drug and successfully avoiding first pass hepatic and gastro intestinal metabolism. Keywords: Solvent casting method, Ketoconazole (KTC), Permeation enhancer, Matrix transdermal patch and FTIR.