Natural organic matter, specifically ortho-quinones organics among them, was considered can participate in the transformation of sulfonamide antibiotics (SAs). Herein, based on targeted oxidizing for ortho-dihydroxyl structures (catechol as the model) upon periodate, an efficient approach for SAs elimination was introduced. Results first indicated the generation of ortho-benzoquinone (o-BQ) within periodate/catechol system progresses readily (the energy barriers for 9.6854 kcal/mol). The near-complete eliminations were observed towards sulfamethoxazole (SMX) in periodate/catechol system (with the rate of 0.4229 min−1) as well as other SAs and exhibited unprecedented resistance to operating parameters. Besides, periodate converts little into toxic low-valent iodate species during the reaction process, and both the cytotoxicity and acute toxicity assays revealed a significant decline in antibiotics bioactivity. Mechanistic insight revealed that o-BQ dominated the degradation process, comprehensive analysis further confirmed Michael addition reaction was the first degradation stage, in which electrons flow from o-BQ to SMX and form covalent bonds upon aniline. Furthermore, several catechol derivatives were used to verify the universality of the mechanism, and their wide distribution in both subsurface and wastewater implies the potential applications. Overall, the mechanisms elucidated behind this research proposed an efficient strategy for eliminating trace SAs in aqueous environments and selectively removing SAs from complex wastewater matrices.