Sulfate radical (SO₄˙⁻) based oxidation technologies have been widely used in the remediation of antibiotic-containing wastewater. Activated persulfates are efficient reagents for achieving SO₄˙⁻, but the storage and transportation of concentrated persulfates present associated safety issues. In this study, bisulfite (BS) was used as an alternative precursor for replacing persulfates, and a simple advanced oxidation system (Fe³⁺/BS) for generating SO₄˙⁻ and hydroxyl radical (HO˙) was formulated and evaluated for removing sulfamethoxazole (SMX) from contaminated water. The initial pH, dosages of Fe³⁺ and BS, as well as the water matrix were investigated to improve the SMX degradation. The results indicated that 1 μmol L⁻¹ SMX was completely removed within 5 min at optimum initial pH of 4.0, Fe³⁺ dosage of 10 μmol L⁻¹, BS dosage of 100 μmol L⁻¹ and temperature of 25 °C. The presence of HCO₃⁻ and natural organic matter (NOM) showed obviously negative effects on SMX degradation, while Cu²⁺ could slightly promote the degradation of SMX if its concentration was in an appropriate range (∼1 μmol L⁻¹). Scavenger quenching experiments confirmed the presence of SO₄˙⁻ and HO˙, which resulted in efficient SMX degradation in the Fe³⁺/BS system. During the radical chain reactions, Fe²⁺ and Fe³⁺ could be converted into each other to form self-circulation in this system. The degradation pathway of SMX by Fe³⁺/BS was proposed including hydroxylation and bond cleavage.