Melanoma is the most aggressive and deadly form of skin cancer. The stratum corneum of the skin is a major obstacle to dermal and transdermal drug delivery. Ultradeformable nanovesicular transferosome has the capacity for deeper skin penetration and its incorporation into hydrogel forms a transgelosome that has better skin permeability and patient compliance. Here, the quality-by-design-based development and optimization of nanovesicular transgelosome of standardized fruit ethanolic extract (PLFEE) for melanoma therapy are reported. Compared with standardized PLFEE-loaded plain gel, the transgelosome displayed optimal pharmaceutical properties and improved skin permeability and tumor regression in B16F10 melanoma-bearing C57BL/6 mice. The results reflect the potential of transgelosome for melanoma therapy.