The focus of this investigation is the development of a fast and reliable extractant screening approach. Phenol extraction is selected as the model process. A quantum chemical conductor-like screening model for real solvents (COSMO-RS) is combined with molecular design considerations. For this purpose, phenol distribution coefficients KD of known phenol extractants are determined experimentally and in silico. Molecular variations of different extractants are tested concerning their effect on KD to facilitate extractant improvement. It is shown that KD depends on the molecular structure of the extractant. Calculations with COSMO-RS provide a qualitative trend of simulated extraction efficiency and even a quantitatively correct description of KD. The simulations for alkylamine components are, however, not accurate, which is a well-known problem. During the screening process, phosphorus containing aliphatic substances, especially the trialkylphosphine oxide compound Cyanex 923, were determined as the most promising phenol extractants, which agrees with the state of the art.