Considering the separation of 1-butanol and water, extraction has received increasing attention because of the advantages of easy operation and low energy consumption. In this work, deep eutectic solvents (DESs) were introduced as hydrophilic solvents for 1-butanol dehydration. The COSMO-SAC model was employed for DESs screening, and choline chloride-urea 1:2 DES (reline) was selected as the corresponding solvent. Via various quantum chemical methods, hydrogen bonds were proven to be the main molecular interactions, wherein a stronger interaction in water + reline was the fundamental for achieving 1-butanol dehydration. Liquid-liquid equilibria were measured at three temperatures, and the results indicated that reline had excellent separation performance especially under conditions of lower temperature or lower water content. Furthermore, the NRTL model was used to correlate experimental data to obtain binary parameters, and the extraction process was simulated. By the investigation of operation parameters, high-purity 1-butanol was obtained via a high recovery rate.