Due to their toxicity and persistence in the environment, phenolic pollutants pose a serious threat to the ecosystem. In this work, the performance of hydrophobic deep eutectic solvents (HDESs) for phenol removal from aqueous effluents is thoroughly investigated using COSMO-RS screening followed by experimental validation. The screening results of 73 HDESs showed that the efficacy of phenol removal is significantly affected by chain length, functional groups, and aromaticity. Trioctylphosphine oxide (TOPO)-based HDESs were found to be the most effective HDESs for phenol elimination combined either with menthol (Men), 1-hexanol (Hex), Decanoic acid (DecA), or Thymol (Thy) all in 1:1 molar ratios. The better phenol elimination abilities of the selected HDESs were confirmed by experimental LLE data obtained at 298.15 K and 101 kPa. In fact, it has been found that there is a positive correlation between extraction efficiency and phenol content. For instance, at a phenol concentration of 7%, TOPO:Men had the highest extraction efficiency (96%). Moreover, the physicochemical properties of the selected HDESs, such as density, viscosity, FTIR, 1HNMR, and TGA, were also measured. The results showed their high thermal stability and low water solubility, which makes them suitable for phenol extraction applications. This study shows that HDESs are capable of removing phenolic contaminants from aqueous effluents in a sustainable and efficient manner and that the selected TOPO-based HDESs are of particular interest for further research and application in phenol removal.