The present study aimed to develop Ketoconazole -loaded ethosomal gel intended to be applied topically for treating skin infections. Ethosomes were prepared using the cold method. The formulation variables were optimized using 3³ factorial design and Design Expert^® software for analyzing the data statistically and graphically using response surface plots. Phospholipid (X1) and ethanol (X2) and propylene glycol (X3) were chosen as the independent variables, while the dependent variables comprised entrapment efficiency (Y1), vesicles size (Y2) and zeta potential (Y3). Ultra-centrifugation was used to assess the encapsulated medication after confirming the presence and size of vesicles. There was a greater increase in value (79.62%) in sonicated particles containing 30% w/w ethanol. The optimized ethosomes were subsequently incorporated into Carbopol^® 940 gel and characterized for rheological behaviour, in-vitro release, ex-vivo skin permeation and deposition. Morphologically, the produced ethosome formulations were consistent when examined by SEM. All of the vesicles met or exceeded the criteria for nanotechnology in terms of size (less than 200nm), polydispersity index (PDI), and entrapment efficiency (of the intended medication). The percentage of Ketoconazole released after 24 hours was significantly decreased (p 0.05) when the ethosomes were included into a variety of gel bases. By contrast, ethosomal gel showed considerably greater anthralin penetration than the other tested preparations (p<0.05). Compared to the ethosomal gel, the drug solution in receptor medium, and the drug hydroalcoholic solution, the total quantity of drug penetrated from the ethosomal gel was around 2.5-, 3.5- and 4.5-fold greater (p<0.05). Stability studies displayed that after 2 months, all of the gels' physicochemical characteristics, including viscosity and color, remained unchanged, passing the tests.