Purpose <p>The aim of this work is to enhance curcumin skin permeability through nanocrystals preparation.</p> Methods <p>The bottom-up nanoprecipitation technique was used. Chitosan amount (X₁) and curcumin amount (X₂) were tested as the independent variables using a 3¹ × 2¹ full factorial design. Particle size (Y₁), zeta potential (Y₂), cumulative amount released (Q_24h) (Y₃) and dissolution efficiency (%DE_24h) (Y₄) were the dependent variables. The optimized formula was further characterized for any chemical or physical incompatibility, transmission electron microscopy, kinetics analysis of the in vitro release data, ex vivo permeability and retention study, the effect of storage at refrigerator, MTT assay and cell cycle analysis. Ex vivo histopathological examination was studied after incorporation in a gel base (FG).</p> Results <p>Curcumin and chitosan were chemically compatible through Fourier Transform Infra-Red Spectroscopy. The selected formula (F3) showed birefringence under the polarized microscope indicating the crystalline form after preparation. Small particle size (155&#xa0;nm), high zeta potential (+ 83.8 mV) and enhanced dissolution (Q_24h = 66.66% and DE_24h = 54.97%) were recorded. Transmission electron microscopy showed semispherical particles with shiny appearance. Ex vivo histopathological examination of curcumin nanocrystals gel proved biocompatibility. The formula also showed potent antiproliferative effect on the tested cell lines with the IC50 of 58&#xa0;µg/mL.</p> Conclusion <p>It could be concluded that curcumin nanocrystal gel is a promising topical delivery system.</p> Graphical Abstract <p></p>