Recently, yolk-shell structured materials with active metal cores have received considerable attention in heterogeneous Fenton-like systems, which have excellent catalytic performance. In this study, we initially attempted the nonsacrificial template synthesis of yolk-shell structured nanoparticles with magnetite cores encapsulated in a mesoporous silica shell (FeO@SiO) via a modified sol-gel process and then evaluated their catalytic activity for acetaminophen degradation in Fenton-like systems. Second, copper nanoparticles were decorated on the surface of the FeO@SiO microspheres (FeO@SiO@Cu) to enhance the catalytic activity. The morphological, structural, and physicochemical properties of the prepared materials were characterized via X-ray diffraction, X-ray photoelectron spectroscopy, field emission scanning electron microscopy, field emission transmission electron microscopy, nitrogen adsorption-desorption isotherms, specific surface area, ζ-potential, magnetic properties, and Fourier transform infrared spectroscopy. The results demonstrated a successful fabrication of the targeted materials. The yolk-shell structured materials possess a spherical morphology with an active core, protective shell, and hollow void. The FeO@SiO and FeO@SiO@Cu variants showed acetaminophen removal rates significantly higher compared to those of their counterparts, i.e., the FeO and FeO@Cu core-shell structures. FeO@SiO@Cu showed that the copper nanoparticles were firmly immobilized on the mesoporous silica shell, dramatically improving the catalytic performance. Both the yolk-shell structured FeO@SiO and FeO@SiO@Cu exhibited good separation and satisfactory regeneration properties, which could be recycled six times without any obvious decline in catalytic activity. Overall, the results of this study suggested that FeO@SiO and FeO@SiO@Cu yolk-shell nanostructures could be promising catalysts for a heterogeneous Fenton-like system by which the removal of emerging contaminants can be greatly improved.