The present investigative work is carried out to formulate and optimize the Paroxetine ethosomal gel using cold method. As a part of the investigation, we used three square design using design expert® 11.0 version software for optimization of individual concentrations of lecithin and ethanol and are considered as the independent variables. Whereas, drug content, entrapment efficacy, and vesicular size are considered as dependent variables which gets altered due to independent variable concentrations. The study was carried out using 14 formulations containing the variable concentrations of lecithin and ethanol. Further, the in-vitro studies of the formulations reveal that F3 having lecithin: ethanol ratio as 100:5 and exhibiting the drug content of 95.285% and entrapment efficacy of 95.354% is considered as optimized. In continuation to the above, F3 exhibits first order release (R2 = 0.951) mechanism with non- Fickian diffusion. The ANOVA studies and polynomial equations in terms of coded equations were generated for the obtained results which reveal the effect of lecithin on the dependent variables and strengthen the statistical data. On the whole, it can be concluded that F3 is optimized and can serve as an effective carrier for transdermal drug delivery of Paroxetine in generating the required therapeutic effect.The present investigative work is carried out to formulate and optimize the Paroxetine ethosomal gel using cold method. As a part of the investigation, we used three square design using design expert® 11.0 version software for optimization of individual concentrations of lecithin and ethanol and are considered as the independent variables. Whereas, drug content, entrapment efficacy, and vesicular size are considered as dependent variables which gets altered due to independent variable concentrations. The study was carried out using 14 formulations containing the variable concentrations of lecithin and ethanol. Further, the in-vitro studies of the formulations reveal that F3 having lecithin: ethanol ratio as 100:5 and exhibiting the drug content of 95.285% and entrapment efficacy of 95.354% is considered as optimized. In continuation to the above, F3 exhibits first order release (R2 = 0.951) mechanism with non- Fickian diffusion. The ANOVA studies and polynomial equations in terms of coded equations were generated for the obtained results which reveal the effect of lecithin on the dependent variables and strengthen the statistical data. On the whole, it can be concluded that F3 is optimized and can serve as an effective carrier for transdermal drug delivery of Paroxetine in generating the required therapeutic effect.