Regulation of recognition events evolving in time and space is vital for living organisms. During evolution, organisms have developed distinct and orthogonal mechanisms to achieve selective recognition, avoiding mutual interference. Although the merging of multiple selection mechanisms into a single artificial host may lead to a more adaptable recognition system with unparalleled selectivity, successful implementation of this strategy is rare. Inspired by the intriguing structures and recognition properties of two well-known biological ion binders—valinomycin and K⁺ channels—we herein report a series of hosts equipped with dual guest selection mechanisms. These hosts simultaneously possess a preorganized binding cavity and a confined ion translocation tunnel, which are crucial to the record-setting K⁺/Na⁺ selectivity and versatile capabilities to discriminate against a wide range of ion pairs, such as K⁺/Rb⁺, K⁺/Ba²⁺, and Rb⁺/Cs⁺. Mechanistic studies verify that the host’s portal is capable of discriminating cations by their size, enabling varied ion uptake rates. The confined tunnel bearing consecutive binding sites promotes complete desolvation of ions during their inclusion into the buried cavity, mimicking the ion translocation within ion channels. Our results demonstrate that the capability to manipulate guest recognition both in equilibrium and out-of-equilibrium states allows the host to effectively discriminate diverse guests via distinct mechanisms. The strategy to merge orthogonal selection mechanisms paves a new avenue to creating more robust hosts that may function in complex biological environments where many recognition events occur concurrently.