To reduce the environmental pollution caused by organic solvents and improve the extraction efficiency, a range of imidazolium-based ionic liquid (IL) combinations of [Omim]+ paired with [Br]-, [BF4]-, [Cl]-, [ClO4]-, [HsO4]-, [NO3]-, [NTf2]-, [OAc]-, [PF6]-, and [TsO]- are explored for the extraction of camptothecin (CPT) using molecular dynamics (MD) simulation and density functional theory (DFT) calculations. It is found that the ILs containing [Br]-, [OAc]-, and [TsO]- anions are the most promising solvents for CPT solvation because they exhibit stronger interaction energy and the lowest self-diffusion coefficient of CPT among all ILs. The microscopic mechanism at the molecular level is revealed based on DFT calculations and MD simulations, and the results demonstrate that the IL (i.e., [Omim][TsO]) containing anions with strong hydrogen bond (HB) acceptability and aromatic ring structure corresponds to both the strongest van der Waals interaction and strongest HB interaction of CPT-anions. Therefore, it is recommended that anions with aromatic ring structures or strong HB acceptability are promising anion candidates, while anions containing electron withdrawing groups and bulky substituents should be avoided. This work provides intermolecular insight into designing and selecting effective ILs for natural insoluble active pharmaceutical ingredient dissolution and extraction in further research.