The present investigation deals with the development of duloxetine ethosome then loading into the transdermal patch to impart lower drug side effect, enhanced bioavailability, avoiding first-pass metabolism. 3 2 factorial design was applied to optimize the formulation. Ethanol (X1) and Phospholipid (X2) were taken as independent variable, Responses are vesicle size (Y2), entrapment efficiency (Y1). Optimum desirability was identified and, an optimized formulation was prepared, characterized and loaded into transdermal patch. The transdermal patch was evaluated for drug content, thickness, folding endurance. Ex-vivo permeation study for the prepared patch was conducted and, the permeation parameters and drug permeation mechanism were identified. The percent of alcohol was significantly affecting all the studied responses while the other factors and their interaction effects were varied in their effects on each response. The optimized ethosomes formulation showed observed values for Y2, Y1 of 161 nm and 98.79% respectively. Ex-vivo permeation of films loaded with optimized ethosomal formulation was superior to that of the corresponding pure drug transdermal Patches. INTRODUCTION: Flexible vesicular carriers are one of the approaches to enhance skin permeability of essential drugs, through the stratum corneum barrier. Liposomes, transfersomes, and ethosomes are three common types of these flexible particles although niosomes, non-ionic surfactant based vesicles, possess similar properties and uses 1. Conventional liposomes are the least among them in their transdermal application since they are confined to the upper layer of the skin stratum corneum and therefore, are topical delivery. Ethosomes are lipid-based vesicular particles containing ethanol in a relatively high concentration and water.