Herein, this work investigated a novel strategy utilizing electrochemical activation of periodate (EC/PI) for effective degradation of sulfamethoxazole (SMX) with wide appliable pH range. The EC/PI system achieved 100% degradation efficiency of SMX under optimum conditions of 7.78 mA/cm² current density, 1 mmol/L IO₄⁻ dosage, and 20 mmol/L Na₂SO₄ as the supporting electrolyte. Strong synergistic effect between applied electric current and IO₄⁻ activation was observed, indicating the robustness of EC/PI system. Through a series of chemical probe experiments and electron paramagnetic resonance analysis, it was revealed that EC/PI is a composite oxidation system with multiple active species, including hydroxyl radical (^•OH), iodate radical (IO₃^•), and singlet oxygen (¹O₂). The production mechanisms of these active species were comprised of two routes: direct production via the electrode supplying electrons and indirect production via hydrogen peroxide (H₂O₂) and superoxide radical (O₂^•−) as intermediates. The EC/PI process was slightly affected by the coexisting substances in the water background, and cycle experiments verified its degradation stability, indicating that this EC/PI system exhibits excellent capacity for treatment of authentic wastewater. Finally, the SMX degradation intermediates and pathways were obtained using mass spectrometry analysis and Gauss theory calculations. These results indicated the establishment of EC/PI system provides an efficient and environmental-friendly strategy for treatment of emerging organic pollutants.