Background: Nimodipine is a vasodilator that is used for the prevention of cerebral vasospasm after subarachnoid hemorrhage. The oral and intravenous administration of the drug is associated with undesirable side effects. So, transdermal delivery using lipid-based nanovesicles, also known as transferosomes, can be thought of as an alternative. Objective: To optimize the formulation of transferosomes using the statistical design of experiments, with the aim of obtaining the most suitable transferosomes for the transdermal delivery of nimodipine. Methods: In the Box-Behenken statistical design, the independent variables were the quantities of nimodipine, phospholipon 90%, and sodium deoxycholate, while the dependent variables were the vesicle size, entrapment efficiency for nimodipine and its flux through the rat's skin. The optimized formulation was characterized through transmission electron microscopy and the deformability index. Results: The optimized formulation of transferosomes suggested by the software consisted of 30 mg nimodipine, 150 mg phospholipon 90% and 15 mg sodium deoxycholate. The resulted values were 248 nm for vesicles size, 81% for entrapment, and 476 μg/cm2/h. Under transmission electron microscopy, transferosomes appeared as vesicles, with a 0.98 deformability index for the optimized formula. Conclusions: Nimodipine can be formulated as transferosomes and efficiently applied for transdermal delivery.