It is a challenging undertaking to screen the best ionic liquid for keratin dissolution, due to the complexity of keratin molecules and the variety of ionic liquids (ILs). Herein, three keratin models and 621 ILs, including 27 cations and 23 anions, were used to evaluate keratin dissolution capability via a screening method based on COSMO-RS. From the prediction results of logarithmic activity coefficients (In gamma) for the three keratin models, it can be concluded that anions play a leading role in keratin dissolution, while cations only have a moderate effect on the dissolution process. The hydroxyl group on the cation side chain has a significant effect on the keratin dissolution capability of ILs. In addition, the experimental solubility of wool keratin in 10 ILs was used to verify the theoretical predictions. Experimentally determined keratin solubility agrees well with the predicted ln gamma. The residual sum of squares (RSS) and R square (R-2) between the In gamma of three keratin models and keratin solubility illustrate that the models glutathione (GSSG) and polypeptide (PP) represent keratin better than cystine (CYS). Ac-, Dec(-), HCOO-, Cl-, BEN-, DMP-, DEP-, DBP-, TOS-, and Br-, with the various cations studied in this work, exhibited particularly good properties for keratin dissolution. Excess enthalpy calculations indicated that the main forces in keratin dissolution in ILs are H bonds, while the contribution of misfit forces and van der Waals forces is a secondary factor.