The aim of the present study is to formulate highly permeable carriers (i.e., transethosomes) for enhancing the delivery of prednisolone combined with tacrolimus for both topical and systemic pathological conditions. A Box–Behnken experimental design was implemented in this research. Three independent variables: surfactant concentration (X1), ethanol concentration (X2), and tacrolimus concentration (X3) were adopted in the design while three responses: entrapment efficiency (Y1), vesicle size (Y2), and zeta potential (Y3) were investigated. By applying design analysis, one optimum formulation was chosen to be incorporated into topical gel formulation. The optimized transethosomal gel formula was characterized in terms of pH, drug content, and spreadability. The gel formula was challenged in terms of its anti-inflammatory effect and pharmacokinetics against oral prednisolone suspension and topical prednisolone–tacrolimus gel. The optimized transethosomal gel achieved the highest rate of rat hind paw edema reduction (98.34%) and highest pharmacokinetics parameters (Cmax 133.266 ± 6.469 µg/mL; AUC0-∞538.922 ± 49.052 µg·h/mL), which indicated better performance of the formulated gel.