Iohexol as an iodinated X-ray contrast agent is widely used, and it is the potential precursor for toxic iodinated disinfection by-products in the disinfection process. In this study, a series of CuFe2O4 catalysts were prepared by sol-gel method with different molar ratios of total metal cations to citric acid ([Men+]T/CA) and employed as heterogeneous catalysts to activate peroxymonosulfate (PMS) for the removal of iohexol. The catalysts were characterized by various technologies, and the effect of [Men+]T/CA molar ratio on the catalysts' properties was explored. The CuFe2O4 synthesized with [Men+]T/CA molar ratio of 1:1 showed the best catalytic activity to PMS, and 95.0% of 1.0 mg/L iohexol was removed within 15 min by using 50 mg/L CuFe2O4 and 20 mg/L PMS. The quenching experiment and electron spin resonance (ESR) spectra indicated the generation of SO4- and OH in the CuFe2O4/PMS system, and the quantity experiments revealed that the generation concentration of SO4- was ten times higher than that of OH. The generation mechanism of SO4- and ·OH were investigated by ATR-FTIR and X-ray photoelectron spectroscopy (XPS) spectra. The effects of catalyst dosage, PMS and iohexol concentration on the removal of iohexol were studied, and various water matrix factors including solution pH, natural organic matter (NOM) concentration and inorganic ions were also considered. Based on the twelve intermediate products of iohexol detected by UPLC-QTOF/MS, the degradation pathway was proposed. The high catalytic activity and reusability of CuFe2O4 indicated that CuFe2O4 activating PMS is an effective and sustainable way for the treatment of iohexol.