In this work, we demonstrate for the first time the abatement of sulfamethoxazole (SMX) induced by stabilized orthosemiquinone radicals (o-SQ •− ) in the MnO 2 -mediated system in the presence of humic acid. To evaluate the performance of different MnO 2 /mediator systems, 16 mediators are examined for their effects on MnO 2 reactions with SMX. The key role of the bidentate Mn(II)o-SQ • complex and MnO 2 surface in stabilizing SQ •− is revealed. To illustrate the formation of the Mn(II)-o-SQ • complex, electron spin resonance, cyclic voltammetry, and mass spectra were used. To demonstrate the presence of o-SQ • on the MnO 2 surface, EDTA was used to quench Mn(II)-o-SQ • . The high stability of o-SQ •− on the MnO 2 surface is attributed to the higher potential of o-SQ •− (0.9643 V) than the MnO 2 surface (0.8598 V) at pH 7.0. The SMX removal rate constant by different stabilized o-SQ • at pH 7.0 ranges from 0.0098 to 0.2252 min −1 . The favorable model is the rate constant ln (k obs, 7.0 ) = 6.002E HOMO (o-Q red ) + 33.744(E LUMO (o-Q) − E HOMO (o-Q red )) − 32.800, whose parameters represent the generation and reactivity of o-SQ • , respectively. Moreover, aniline and cystine are competitive substrates for SMX in coupling o-SQ •− . Due to the abundance of humic constituents in aquatic environments, this finding sheds light on the low-oxidant-demand, low-carbon, and highly selective removal of sulfonamide antibiotics.