A sensor with a red-emission signal is successfully obtained by the solvothermal reaction of Eu3+ and heterofunctional ligand bpydbH2 (4,4′-(4,4′-bipyridine-2,6-diyl) dibenzoic acid), followed by terminal-ligand exchange in a single-crystal-to-single-crystal transformation. As a result of treatments both before and after the metal–organic framework formation, accessible Lewis-base sites and coordinated water molecules are successfully anchored onto the host material, and they act as signal transmission media for the recognition of analytes at the molecular level. This is the first reported sensor based on a metal–organic framework (MOF) with multi-responsive optical sensing properties. It is capable of sensing small organic molecules and inorganic ions, and unprecedentedly it can discriminate among the homologues and isomers of aliphatic alcohols as well as detect highly explosive 2,4,6-trinitrophenol (TNP) in water or in the vapor phase. This work highlights the practical application of luminescent MOFs as sensors, and it paves the way toward other multi-responsive sensors by demonstrating the incorporation of various functional groups into a single framework.