Whitening materials cannot easily cross the skin barrier (stratum corneum) to reach melanocytes in the basal layer for inhibiting melanin production. This study aims to construct a novel deformable liposome using polyglyceryl‐3‐methylglucose distearate as an edge activator and a hydrogel containing hyaluronic acid (HA) and hydroxyethyl cellulose (HEC), as well as to investigate the synergistic effect of this system on the delivery of a cysteine derivative, methyl‐2‐acetylamino‐3‐(4‐hydroxyl‐3,5‐dimethoxybenzoylthio)propanoate (MP) as a whitening agent. The optimized deformable liposome (DL2) contains 10% edge activator and has a particle size of 78.2 ± 2.7 nm, a zeta potential of −29.9 ± 1.8 mV, a polydispersity index of 0.248, and an entrapment efficiency of 90.7 ± 1.7%. MP‐loaded DL2 has higher stability and deformability than DL2 without MP, as well as exerting a higher whitening effect than that observe with MP alone. In addition, MP‐loaded DL2 is incorporated into a hydrogel in a dual drug‐delivery system and the stability after hydrogel incorporation is evaluated. In Franz cells, the MP‐loaded deformable liposome‐hydrogel complex shows the highest skin permeation and penetration of MP. Practical Applications: In general, it is very difficult for whitening agents to penetrate a skin layer for reducing skin pigmentation. It is important to transfer whitening agents to the basal layer without causing physical damage to the skin. Deformable liposomes containing 10% polyglyceryl‐3‐methylglucose distearate in a hydrogel complex maximize the skin permeation of a cysteine derivative as a whitening agent. This finding indicates that the deformable liposome‐hydrogel complex is a potential delivery system for treatment of skin hyperpigmentation. The penetration mechanism of drugs in the skin by deformable liposome‐hydrogel complexes is as follows: Hydrogel hydrates stratum corneum to secure the route of drugs or nanocarrier permeation. polyglyceryl‐3‐methylglucose distearate as an edge activator enhances the fluidity of the stratum corneum lipid layer and the deformability of liposome. The edge activator‐based deformable liposomes pass through the stratum corneum stably.