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This study aimed at developing curcumin nanoethosomes (Cur-Ets) with superior skin permeation intended for melanoma treatment. Although curcumin is active against many types of skin cancers, a suitable topical formulation is still lacking due to its hydrophobicity and poor skin permeation. The formulation was characterized using Scanning Transmission Electron Microscopy (STEM), atomic force microscopy (AFM), ATR-FTIR, DSC and XRD.  In vitro  skin permeation was carried out using human skin, and the cytotoxicity of the formulation was evaluated on human melanoma cells (SK-MEL28). The vesicle size and zeta potential of the Cur-Ets were determined as 67 ± 1.6 nm and −87.3 ± 3.3 mV, respectively. STEM and AFM analysis further support the size and morphology of the formulation. Curcumin’s compatibility with formulation additives was confirmed by ATR-FTIR analysis. In addition, DSC and XRD analyses showed successful drug encapsulation in nanoethosomes. The drug encapsulation efficiency was determined as 87 ± 0.9%. The skin permeation of curcumin from Cur-Ets showed a superior flux (0.14 ± 0.03 µg cm −2  h −1 ) compared to the control ( p  &lt; 0.05). Cytotoxicity of the formulation demonstrated a time-dependent and concentration-dependent antiproliferative activity against melanoma cells. The developed Cur-Ets is suggested as a promising topical formulation for melanoma treatment.