Abstract: As a bioactive component extracted from the seed of milk thistle, silymarin has many pharmacological functions, such as liver-protective and cholagogic effect. It is categorized as a class of flavonoids, among which silybin is one of the main components. Efficient extraction of silybin with a type of new and green solvent natural deep eutectic solvent (NADES), as well as mechanism discussion were explored in this study. With the degreased milk thistle seed shell powder as raw material and using HPLC for silybin analysis, NADES composed of choline chloride/1,4-butanediol was screened out as optimal solvent for silybin extraction. On the basis of single factor experiments, Box-Behnken Design from response surface methodology was used for process optimization. The generated model predicated that the highest silybin yield of 4.29% would be achieved with solid-liquid ratio of 1:20 g/mL, at 77 °C for 5.6 h. The result from verification experiment was about 4.30%, which fitted well with the prediction. Then, based on conductor-like screening model for segment activity coefficient (COSMO-SAC), structure and energy optimization of silybin and solvent were attempted. The logarithms of infinite dilution activity coefficients in the two solvents, chloride/1,4-butanediol and the traditional organic solvent ethanol, were −6.922 and −6.043, and the intermolecular interaction energies were −51.62 and −25.47 kJ/mol, respectively, which would provide insight into the mechanism explaining performance difference of the solvents during extraction.