Aim: The optimisation and evaluation of ethosomal nanogel (NGs) for topical delivery in skin cancer. Methods: The formulations were optimised by employing 3-factor, 3-level Box Behnken design for responses of vesicle size, and fluxes. They characterised in vitro and evaluated for drug release, permeation and retention, skin penetration of ethosome, electron microscopy, texture analysis, and in vitro cytotoxicity. Results: The optimised formulation exhibited z-average 125.67 +/- 10.43 nm, apparent zeta potential -17.1 +/- 2.61 mV, average flux of drug loaded ethosome were 54.72 +/- 5.45 and 59.83 +/- 6.09 mu g/cm(2)/h. Further, Rhodamine B loaded ethosome penetrated deeper up to 183.82 mu m. The NGs texture analysis showed index of viscosity 225.45 g.s, firmness 209.34 g, cohesiveness -189.48 g, and consistency 59.45 g.s. The optimised ethosome NGs exhibited significant anti-cancer effect in B16-F10 murine tumour cell line (p < 0.05). Conclusion: Ethosomal NGs could be promising for skin cancer treatment.