An effective and environmentally benign methodology for the synthesis of isoxazol‐5(4H)‐one derivatives has been developed using a ZnO@Fe3O4 core–shell nanocatalytic system. The one‐pot, multicomponent reaction of an aromatic/heterocyclic aldehyde, hydroxylamine hydrochloride and ethyl acetoacetate under aqueous conditions at slightly elevated temperature resulted in the formation of title compounds in extremely good yields. The present new protocol is environmentally friendly as it offers heterocyclization with some interesting promising features such as safety, atom efficiency, low cost, mild conditions, minimal waste, catalyst recyclability, water as a solvent, easy workup and possession of excellent functional group tolerance for the synthesisis of structurally diverse isoxazole derivatives. All products were characterized by spectral and analytical methods. A representative title derivative was studied for its structure by single crystal X‐ray diffraction method.