The solvation mechanisms of aspirin and etomidate in four combinations of [Emim] and [BuGun] paired with [OAc] and [NTf] were systematically studied by molecular dynamics simulations and DFT calculations. It was shown that the favorable solvation of aspirin and etomidate correlated well with hydrogen-bond (H-bond) basicity of anions and the H-bond acidity of cations, respectively. Wherein, the H-bond between aspirin and [OAc] anion with high H-bond basicity possessed covalent feature, so ILs containing [OAc] anion has the best effective in solubilizing aspirin. However, H-bond interactions between etomidate and cations exhibited an electrostatic dominant, and moderate cation–anion interaction could weaken it. Accordingly, for etomidate, the best ILs solvent comprised a weakly interacting anion and a cation with strong H-bond acidity, that is, [BuGun][NTf]. This solvation difference was because aspirin with carboxyl group displayed strongly H-bond donating characteristic, whereas etomidate with no active hydrogen protons mainly formed H-bond with cations. Additionally, we found that π–π stacking interactions were of secondary importance for the solubilization of etomidate, but little for aspirin. These simulations will be helpful for experimental design new ILs to solubilize some drugs with aspirin-like or etomidate-like structures.