Background: Silymarin is the extract from seeds of Silybum marianum L. Gaertn. and it has been used for decades as hepatoprotectant. Recently, it has been proposed to be beneficial in type 2 diabetes patients. However, silymarin is a poorly water soluble drug with limited oral bioavailability. In this study, nanostructured lipid carriers were proposed to enhance its solubility and intestinal absorption. Methods: Nanostructured lipid carriers were made of Stearic acid:Capryol 90 as lipid mixtures and Brij S20 as surfactant. Formulations were physically and chemically characterized. Stability and in vitro release studies were also assessed. In vitro permeability and Caco-2 cellular uptake mechanism were investigated. Results: Obtained results were based on size, homogeneity, ζ-potential and EE%. Nanostructured lipid carriers could be orally administered. No degradation phenomena were observed in simulated gastrointestinal fluids. Storage stability of suspensions and lyophilized products was also tested. Glucose was selected as best cryoprotectant agent. About 60% of silymarin was released in 24 h in phosphate buffered saline. In vitro parallel artificial membrane permeability assay experiments revealed that the nanocarrier enhanced the permeation of Silymarin. Caco-2 study performed with fluorescent nanoparticles revealed the ability of carrier to enhance the permeation of a lipophilic probe. Cellular uptake studies indicated that active process is involved in the internalization of the formulation. Conclusions: The optimized nanostructured lipid carriers showed excellent chemical and physical stability and enhanced the absorption of silymarin.