Despite the fact that the complexation of ammonium cations with ionophores like crown ethers plays an important role in biological and industrial processes, there is still a lack of theoretical methods to reproduce or even predict the host–guest complex structures or their thermodynamic stabilities in an accurate manner. Hence, the development of ionophores has often relied on a trial‐and‐error approach and the synthetic efforts associated with this have been enormous, so far. Therefore, theoretical methods for the reliable prediction of binding affinities of crown ether derivatives with ammonium ions would be an indispensable tool for the rational design of new receptors with tailored properties. Here, we suggest a computationally efficient but still accurate theoretical approach. It is tested for a model system consisting of 18‐crown‐6 ether and an ammonium cation, but is invented for application to much larger complexes. The accuracy of various approximate quantum‐chemical methods, based on density functional theory (DFT) and many‐body perturbation theory, is evaluated against the gold standard CCSD(T) in the basis set limit as internal reference. An important aspect is the consideration of dispersion interactions in DFT methods, for which the dispersion‐correction by Grimme was employed. For all selected methods, the basis‐set dependence of calculated interaction energies was investigated. © 2015 Wiley Periodicals, Inc.