Nimodipine is a vasodilator medicinal agent approved for the prevention of cerebral vasospasm, a major risk factor that causes deaths in patients diagnosed with subarachnoid hemorrhage. The current marketed products of this drug are associated with challenges such as frequent dosing orally, or continuous infusion through central vein. Therefore, transdermal delivery of nimodipine via transferosomes can overcome these difficulties. Solvent evaporation-hydration method followed by sonication was applied for the preparation of transferosomes. The aim of present study is to investigate and optimize the processing parameters of this method through the utilization of Design-Expert software. Box-Behnken statistical design was selected for this purpose to study the hydration temperature, speed of rotation, and hydration time as independent variables, each at three levels. The vesicles sizes (VS), polydispersity index (PDI), and entrapment efficiency (EE) of nimodipine were the dependent variables. After statistical analysis of the obtained data, a batch was formulated according to the selected, optimized variables, and then the responses were compared to those predicted by the software. This batch was subjected to further characterization by transmission electron microscopy (TEM), degree of deformability and permeation through an excised skin of rat. The study showed that transferosomal formulations were within the nanoscale for VS of 95.4 - 914.0 nm with PDI of 0.0897 – 0.624% and EE was 65.2 - 98.3%. The chosen response ranges to optimize the processing parameters were 200.0 - 250.0 nm for VS, 0.1 – 0.4% for PDI and 80.0 - 100.0% for EE.  The resulted values of the batch formulation were comparable as 197.0 nm, 0.01% and 91.4%, respectively. In addition, TEM revealed bilayer vesicular structure, degree of deformability was 0.98 and permeation calculated as the flux of nimodipine was 513 μg/cm2/h. In summary, this study demonstrates that in addition to addressing qualitative and quantitative concerns, optimizing the processing parameters can yield nimodipine-loaded transferosomes to achieve the desired properties of the transferosomes.