Resveratrol (RSV) is a natural polyphenolic compound with high affinity to hepatocytes. It has numerous benefits as anticancer, antioxidant, immunomodulatory and cardioprotective actions. Nevertheless, RSV therapeutic applications are hindered by its low solubility, light sensitivity and extensive first-pass metabolism. Cubosomes are colloidally stable dispersed liquid crystalline nanoparticles. The incorporation of RSV into cubosomes could overcome some of its physicochemical limitations. A Design-Expert® software was applied to optimize cubosomes in terms of particle size and encapsulation efficiency (EE%). The used model proved its suitability in predicting optimum cubosomal size. The prepared cubosomes showed an enhanced HepG2 cytotoxicity except at particle size of ≈20nm. Different endocytic pathways mechanisms as macropinocytosis, clathrin-mediated endocytosis and caveolae-mediated endocytosis were identified in the cellular uptake of RSV cubosomes depending on particle size. Caveolae-mediated transport was shown to have a significant effect on RSV cubosomes internalization efficiency and cytotoxicity.