Screening deep eutectic solvent (DES) is significant for separation process, due to its large number of potential combinations. In this work, 49 DESs were screened for the extractive desulfurization based on the COSMO-RS model. The distribution coefficient, selectivity, and performance index were derived from the mass-based liquid liquid equilibrium of DES involved systems. DES TBPB:DMF(1:3) showed the highest performance index and was screened as the extractive solvent. Its performance was interpreted from the analysis of its alpha-profile and alpha-potential, and its desulfurization ratio can reach up to 82.1%, determined by experiment, when the initial sulfur content in the model fuel was 500 ppm. After 3 stages of extraction, the sulfur content was remarkably reduced to < 10 ppm. The desulfurization ratio kept almost constant after 5 regeneration cycles, indicating its excellent reusability.