Desymmetrization of a symmetric skeleton enables late-stage functionalization of molecules. However, reagent-controlled desymmetrization by site-selective reactions of symmetric molecules remains a difficult synthetic strategy. Here, we found that complete confinement of a symmetric molecule within a coordination cage can desymmetrize the guest conformation, making it possible to site-selectively activate or protect the otherwise equivalent reaction sites of calix[4]arene derivatives. Multistep, one-cage reactions also demonstrated the transformation of an AAAA-type calix[4]arene into a lower symmetry ABAC-type one.