αNβN is widely used as a typical mineral flotation agent in mining extraction areas, which causes serious environmental risks. In this study, natural hydrophobic deep eutectic solvents (HDES) were innovatively used as extractants to remove αNβN from wastewater. A total of 120 HDES candidates were initially screened via COSMO-RS simulations and validated by batch extraction tests, identifying Dec:Thy (1:3 mol:mol) as the most efficient formulation. Under optimal conditions (pH 7, 25 °C, HDES-to-water ratio 1:50), this HDES achieved over 90% αNβN removal within 1 min of mixing. Characterization (DSC, TGA) confirmed its thermal stability and low viscosity, facilitating rapid phase separation. Reusability experiments further demonstrated that the HDES maintained above 90% extraction efficiency over at least eight consecutive cycles. Molecular dynamics simulations showed that the extraction process was mainly driven by van der Waals forces, with some hydrogen bonding as an aid to enhance the affinity of HDES for αNβN. These findings highlight a green, safe, and effective approach for remediating αNβN-contaminated mining wastewater and underscore the potential of HDES as next-generation extractants for organic pollutants.