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 quadrupole 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.