Natural deep eutectic solvents (NADES) represent a promising group of green solvents employed for the extraction of bioactive compounds from medicinal plants. Due to the wide range of polarities of investigated solutes, and an outstanding number of combinations of NADES components, fine tuning and selection by software for modeling and evaluation of thermodynamic properties of solvents and solutes is a necessary step preceding the extraction from real samples. In this study, four hydrophilic NADES were chosen for the prediction of solubility of 19 bioactive compounds from Mediterranean plants, which was performed by COSMO-RS software. NADES structure optimization was performed by pseudocomponent approach and individual constituent approach. Change of hydrogen bond donor components of NADES did not show a significant influence on the solubility of screened solutes. According to both approaches, the investigated systems represent promising solvents for extraction of hydrophilic and moderately lipophilic flavonoids, terpenoids, and phenylpropanoids, while being unsuitable for extraction of the most lipophilic (logkow ≥ 4) natural products and compounds lacking polar functional groups due to the absence of sites participating in hydrogen bond formation.