Antibiotic is an important risk source of ecology and human health, with low concentration of environment and big health risk. Sulfamethoxazole(SMX) has become one of the most frequently detected antibiotics. Advanced Redox process with strong redox ability, low secondary pollutants and eco-friendly properties have been considered as an efficiency strategy. Aiming to develop renewable-energy-based processes, using natural light triggered chemical reactions are attracting more attentions. Spinel structures with narrow band gap, low cost, controllable performance have made them suitable as catalysts in various reactions. However, high electron-hole recombination rate and low quantum yield often lead to poor reaction efficiency. There are ﬁve strategies can be used to enhance their properties, and designing the morphologies and Changing the compositions strategies are considered as more efficient strategies. In order to reduce the residual SMX in water, novel multinary spinel Cu0.5Zn0.5Fe2O4 hollow microspheres with different internal structures (solid, yolk-shell and double-shelled microspheres) were fabricated by a facile self-templated solvothermal and annealing method. The formation mechanism and the relationship between hollow structures with different interior architectures and photocatalytic performance were illustrated based on the analysis of TAS, EPR, PL and DFT. The results showed that when evaluated as the catalytic materials for degradation of SMX, the double-shelled Cu0.5Zn0.5Fe2O4 hollow microspheres show significantly enhanced performance because of its higher surface area, higher charge separation efficiency, more effective light absorption and long radical lifetime. The current research provides new insight into utilizing multinary spinel structures as eﬃcient photocatalysts for the removal of harmful antibiotics in water.