Treatment of antibiotic contaminants from water has become an urgent problem due to that antibiotic pollution may threaten the ecosystem. This study explored the feasibility of enhancement of boron-doped diamond (BDD) anode system for antibiotic removal by utilization of by-product oxygen and natural pyrite catalyst. Sulfamethazine (SMZ), one of commonly detected antibiotics in the aquatic environment, was selected. Completed degradation of SMZ was achieved within 60 min, when 3 g/L pyrite was added into BDD-nickel foam (NiF) electrochemical system. The pseudo first-order reaction rate constant for SMZ degradation in BDD-NiF-pyrite electrochemical system was approximately 9 times higher than that in BDD-NiF electrochemical system. The optimal conditions of BDD-NiF-pyrite electrochemical system for SMZ degradation were: current intensity of 50 mA, pyrite dosage of 3 g/L, initial pH = 3, and reaction time of 60 min at room temperature (25 ± 1 ℃). The ^{radical dot}OH and O₂^{radical dot−} radicals were responsible for SMZ degradation. SMZ degradation intermediates were identified. Possible SMZ degradation pathways were also proposed. Furthermore, in vivo pharmaceutical activity removal of SMZ was assessed by zebrafish inflammation model. SMZ before treatment exhibited anti-inflammatory activity while lost it after treatment. This study offered an alternative approach to boost the BDD electrochemical oxidation of antibiotic-contaminated water.