In this work, the bimetallic oxide CuFeO2 was synthesized by simple hydrothermal synthesis and utilized to activate peroxydisulfate (PDS) for the sulfamethazine (SMT) degradation in water. The influence of some key factors such as CuFeO2 dose, PDS concentration and initial pH on the degradation of SMT was investigated. In particular, the CuFeO2/PDS system was capable of effectively degrading SMT under neutral and weak alkaline conditions. The mechanism of the CuFeO2/PDS system was revealed by quenching experiments and ESR tests. It involves a combined radical and non-radical mechanism with multiple active species (SO4•−, HO•, O2•− and 1O2) acting together. A synergistic interaction between iron and copper on the CuFeO2 surface accelerated the conversion of Fe(III) to Fe(II), which is one of the advantages of CuFeO2 over monometallic oxides. Furthermore, simulated experiments for the SMT degradation were conducted in different water matrices, and the effects of some inorganic ions (e.g. Cl-, SO42- and HCO3-) and humic acid were also explored. Exceptionally, HCO3- played a facilitating role for the removal of SMT. Finally, the CuFeO2/PDS system still exhibited superior performance after five cycles of testing. Overall, this study provided a cost-effective and promising strategy for the removal of antibiotics from the aqueous environment.