Active-in-cyclodextrin-in-transfersomes (DCTs), which encapsulated phenylethyl resorcinol (PR) and resveratrol/hydroxypropyl-β-cyclodextrin (RSV/HP-β-CD) inclusion complexes in the phospholipid bilayer and aqueous compartments of the transfersomes, were prepared by thin film hydration using lecithin, cholesterol, and surfactant as encapsulation materials. The effects of edge activator, their concentrations and addition methods on the particle size, PDI, Zeta potential and encapsulation efficiency of DCTs were studied. Results show that the particle size of DCTs prepared by 0.012 mol/L Tween 20 is 112.43 nm, PDI is 0.16, Zeta potential is -34.90 mV, and the high entrapment efficiency of PR and RSV are achieved as 77.07% and 60.67%, respectively. Through in vitro release, transdermal, cytotoxicity and melanin content in B16-F10 cells of DCTs, it was found that DCTs achieved drug sustained release and prevented drug degradation, reduced the permeability difference of transdermal delivery of combination drugs, decreased the cytotoxicity of free drugs, enhanced the synergistic effect of the combination drug, and reduced the melanin content of B16-F10 cells.