We developed an ethosome formulation that acts as a metformin carrier and studied in vitro skin penetration. We also wanted to assess the anticancer efficacy of the best ethosomal formulation when given topically to animals with chemically generated skin cancer. We used a statistical Box-Behnken experimental design with three variables at three levels: lecithin, cholesterol, and a combination of ethanol and isopropyl alcohol concentrations. All formulations were created to calculate the entrapment efficiency, zeta potential, vesicle size, and drug release percentage after 1, 2, 4, 8, and 24 hours. The formulations' vesicles ranged in size from 124 ± 14.2 nm to 560 ± 127 nm, with entrapment effectiveness of 97.8 ± 0.23% to 99.4 ± 0.24% and drug release rates of 38 ± 0.82% to 66 ± 0.52% after 8 hours. All formulations were entered into the Box-Behnken software, which selected three formulations and assigned one as the ideal formula. Metformin-loaded ethosomal gel has a higher anticancer effect in vivo against skin cancer than the gel formulation containing free metformin. Lower lecithin, high ethanol and isopropyl alcohol, and moderate cholesterol levels increased penetration rate. Overall, we can conclude that metformin-loaded ethosomes are a promising remedy for treating skin cancers, and more studies are warranted to approve this activity in other animal models of skin cancers