A rational multiscale method is proposed for selecting an economical and sustainable solvent for the direct hydration of cyclohexene. At the molecular scale, liquid-liquid phase equilibrium was estimated using group contribution methods to rapidly screen the potential solvent candidates from a range of organics using a novel evaluation index. At the reactor scale, these candidates were experimentally investigated to pick out the solvents that could significantly improve the conversion, without introducing side reactions and deactivating the catalyst. At the process scale, the total annual cost and CO2 emission were calculated to evaluate the eco-efficiency. Using this new multiscale method, acetophenone was selected as an eco-efficient solvent from over 100 organics, resulting in the reduction of TAC by 7.8% and CO2 emission by 16.9% in the production process. Also, acetophenone led to the increase of cyclohexanol yield from 12.3% to 27.6% without the occurrence of side reactions or catalyst deactivation.