The exfoliated graphite loaded CoFe2O4(CoFe2O4-EG) was prepared as a heterogeneous catalyst to activate peroxymonosulfate (PMS) for the catalytic degradation of sulfamethoxazole (SMX) in water in this paper. First, several key influence factors were investigated including CoFe2O4-EG particles dosage, PMS concentration, initial solution pH, initial SMX concentration and co-existing ions. Besides, the removal efficiency and mineralization efficiency of SMX (10 mg/L) exceeded 99% and 30.9%, respectively on the conditions of 0.6 g/L CoFe2O4-EG, 0.4 mM PMS, and initial solution pH 6.0. Meanwhile, the catalytic material showed high recyclability for the SMX removal in the CoFe2O4-EG/PMS system. Then, the CoFe2O4-EG catalyst was characterized by SEM, EDS, BET, XRD, and XPS. Furthermore, the possible reaction mechanism in CoFe2O4-EG/PMS system was studied through quenching tests and electron paramagnetic resonance (EPR) and XPS analyses. Finally, seven major degradation intermediates of SMX were detected by liquid chromatography coupled with quad-rupole time-of-flight mass spectrometry technologies (LC-QTOF-MS/MS) and three possible degradation pathways in CoFe2O4-EG/PMS system were proposed. In brief, this study suggests that the CoFe2O4-EG material had a high potential in PMS activation for antibiotics wastewater treatment.