Silymarin recognized for numerous activities, but the use is limited due to poor aqueous solubility, inefficient intestinal permeability, and low-erratic bioavailability. The aim of the current research was formulation of spray-dried nanoemulsion to enhance the solubility of silymarin. The nanoemulsion was prepared by aqueous titration method, spray died and characterized for thermal analysis by diffraction scanning calorimetry, crystallography analysis by x-ray diffraction, surface morphology by scanning electron microscopy. The reconstitution properties were determining for droplet size, polydispersity index and microscopic structure. Optimized nanoemulsion composed of 15% v/v of oil, 33% v/v of Smix and 52% v/v of distilled water demonstrated lowest droplet size (52.4 ± 1.63 nm) and polydispersity index (0.112), optimum viscosity (23.37 ± 2.36 cps), maximum % transmittance (94.55), optimum cloud point (88°C) and cumulative % drug release (98.43%). The microscopic structure of spray-dried nanoemulsion after reconstitution in distilled water revealed spherical shape free from any aggregation. Spray-dried nanoemulsion demonstrated amorphous sate of silymarin after fabrication into solid state. The cumulative % release of silymarin was significantly higher than marketed conventional suspension (Limarin). The developed spray-dried nanoemulsion was robust and stable for a period of 3 months that could be recommended for oral administration of silymarin after further study. Solids are preferred over liquid dosage form; the formulation may offer better patient compliance over liquid nanoemulsion. In addition, the in-vitro cytotoxicity study revealed more cytotoxicity of SD-NE than plain silymarin against HepG2 cell line after 48 h of incubation. Moreover, the HepG2 cellular uptake silymarin was found to be substantially higher from NE when compared to the plain silymarin. Further, silymarin loaded SD-NE could be potential approach against hepatic cancer.
 Keywords: Silymarin, spray-dried nanoemulsion, dextran, phase diagram, solubility, stability