Precise binding towards structurally similar substrates is a common feature of biomolecular recognition. However, achieving such selectivity—especially in distinguishing subtle differences in substrates—with synthetic hosts can be quite challenging. Herein, we report a novel design strategy involving the combination of different rigid skeletons to adjust the distance between recognition sites within the cavity, which allows for the highly selective recognition of hydrogen‐bonding complementary substrates, such as 4‐chromanone. X‐ray single‐crystal structures and density functional theory calculations confirmed that the distance of endo‐functionalized groups within the rigid cavity is crucial for achieving high binding selectivity through hydrogen bonding. The thermodynamic data and molecular dynamics simulations revealed a significant influence of the hydrophobic cavity on the binding affinity. The new receptor possesses both high selectivity and high affinity, which provide valuable insights for the design of customized receptors. Endo‐functionalized hosts with different rigid skeletons were successfully synthesized. The well‐controlled distances of the recognition sites within the hydrophobic cavities enable the highly selective recognition of structurally similar guests. This approach presents a viable solution for achieving the precise recognition of specific guests in aqueous environments through adjustments in the distance of recognition sites.