In this study, expanded perlite supported oxygen vacancies-CuFe2O4 (OVs-CFEp) was synthesized via a simple method and utilized as floating catalyst to activate peroxymonosulfate (PMS) for the removal of sulfamethazine (SMT) under visible light irradiation. OVs-CFEp/Vis/PMS synergy presents much superior performance than that of OVs-CFEp/Vis system and OVs-CFEp/PMS system. PMS was efficiently activated by OVs-CFEp at a wide range of pH values, while the degrading rate of SMT was up to 95% in OVs-CFEp/Vis/PMS system. Oxygen vacancies and ·O2− accelerated the conversion of Fe(III)/Fe(II) and Cu(I)/Cu(II). The combination of the floating loader boosted light absorption capacity and sufficiently prevented metal ions leaching, which was all beneficial to enhance catalytic performance and recyclability. Besides, the reactive oxygen species were investigated systematically, proving that visible light and OVs-CFEp could activate PMS to produce ·SO4−, ·OH, O2·−, and 1O2 reactive species. Furthermore, based on intermediates identification and Density Functional Theory (DFT) calculation, three types and seven main degradation pathways involving cleavage of bond, SMT molecular rearrangement, and hydroxylation reaction were proposed. So this high photo-absorbing catalyst coupling with advanced oxidation progress was promising for extensive environmental remediation.