Ionic liquids (ILs), molten salts that are liquid at room temperature, are considered as a potential green replacement for toxic volatile organic compounds in many applications. These liquids exhibit unique properties such as negligible vapor pressure, nonflammability, wide liquid range, high thermal and chemical stabilities, and high solvating capacities for in organic, organic, and polymeric compounds. In this paper, computer-aided molecular design of potential ILs for cellulose dissolution was performed. A quantitative structure−activity relationship (QSAR) model was first developed to predict cellulose solubility in ILs using the group contribution (GC) and artificial neural network (ANN) methods. A mixed integer nonlinear programming (MINLP) problem was then formulated with an objective function that maximizes the QSAR model. The solution to the MINLP problem given by genetic algorithm (GA) corresponded to the optimal ILs structure for cellulose dissolution. For example, the cellulose solubility in ILs developed in the present work was at least 1.2 times experimentally higher than that of the best ILs reported for cellulose dissolution. In addition, the addition of cellulose compatible organic cosolvent such as DMSO could enhance the cellulose solubility up to 4 times as compared to that of conventional ILs/cosolvent system. Moreover, the similar degree of polymerization of regenerated and native celluloses indicated that the developed ILs in this study were nonderivatizing solvents for cellulose dissolution.