Sulfamethoxazole (SMX), a representative sulfonamide antibiotic, has been identified as a new kind of persistent pollutant with property of hard biodegradation and hydrolyzation. Conventional methods cannot remove it well. In this study, the performances and mechanisms for SMX degradation were examined by persulfate (PS) activation with nanoscale zero-valent iron (nZVI) at various conditions including dosages of nZVI and PS, pH value, and initial SMX concentration. Results showed that about 88.4% SMX (10 mg/L) was removed by nZVI/PS system (0.10 g/L nZVI, 1.0 mM PS) within 120 min compared to 63.1% by nZVI alone system under room temperature. Lower initial SMX concentration and higher PS concentration were beneficial to the degradation of SMX, while pH (from 3.11 to 9.33) and nZVI dosage (from 0.05 to 0.30 g/L) had little effect. Radical quenching experiment and electron spin resonance test demonstrated that the degradation of SMX was attributed to sulfate radicals (SO 4 ·− ) and hydroxyl radicals (·OH) produced in this system. SMX reduction reaction by nZVI in nZVI/PS process was proved by reductive-oxidative degradation experiment and HPLC test, and the reduction product could be oxidized by SO 4 ·− and ∙OH to other products even to H 2 O and CO 2 . Further, probable removal mechanisms have also been proposed. This study manifests that nZVI/PS system is effective for SMX removal and may provide some ideas for understanding the transformation process of antibiotic in iron-based advanced oxidation processes.