Sulfamethazine (SMT), widely used for treating diseases by bacterial infections, is difficult to degrade with the traditional water treatment process completely. Catalytic ozonation with synthesized maghemite-supported manganese oxides (MnxOy/gamma-Fe2O3) as the catalyst could degrade 100% SMT in 30 min and remove 61.9% TOC in 90 min. Moreover, the TOC removal ratio was 1.79 times higher than that with ozonation alone. The SMT mineralization increased with increasing the ozone dosage, catalyst dosage, and pH of the solution, but it decreased with increasing the SMT concentration. Furthermore, the generated hydroxyl radical contributed to SMT mineralization. The -OH on the surface of MnxOy/gamma-Fe2O3 could further react with O3 to trigger a series of reactions and generate the reactive species. The polyvalent manganese provided the electrons for O3 to produce the reactive species. The degradation process of SMT mainly consisted of de-sulfuration and hydroxylation. The toxicity of final intermediates was negligible compared with that of SMT. The anions or the humic acid in the solution could affect SMT mineralization. The excellent catalytic activity, reusability, and stability of MnxOy/ gamma-Fe2O3 catalysts lay a good foundation for practical application in the future.