Micro/nanomaterials with multilayer core-shell structures are receiving widespread attention due to their potential in energy storage and conversion systems. However, simple fabrication of multilayered core-shell structured micro/nanomaterials with a consistent composition still faces a great challenge. Herein, a simple one-step solvothermal method is used to fabricate Cu-based metal organic framework multilayer core-shell microspheres (Cu-MOF-MCSMSs) as efficient oxygen reduction reaction (ORR) catalysts. The systematic structural evolution of Cu-MOF-MCSMSs is from microspheres to core-shell microspheres and then to multilayer core-shell microspheres. Additionally, different transition metal cations and anions can also influence the structures, compositions and thus ORR activities of the synthesized MOFs. The representative Cu-MOF-MCSMSs exhibit high ORR activity and cycling stability. The simple method can provide a good guide to fabricate other micro/nanomaterials with multilayer core-shell structures and desirable properties.