Sulfide control is a significant problem in urban sewer management. Although in-sewer dosing of chemicals has been widely applied, it is prone to high chemical consumption and cost. A new approach is proposed in this study for effective sulfide control in sewers. It involves advanced oxidation of ferrous sulfide (FeS) in sewer sediment, to produce hydroxyl radical (·OH) in-situ, leading to simultaneous sulfide oxidation and reduction of microbial sulfate-reducing activity. Long-term operation of three laboratory sewer sediment reactors was used to test the effectiveness of sulfide control. The experimental reactor with the proposed in-situ advanced FeS oxidation substantially reduced sulfide concentration to 3.1 ± 1.8 mg S/L. This compares to 9.2 ± 2.7 mg S/L in a control reactor with sole oxygen supply, and 14.1 ± 4.2 mg S/L in the other control reactor without either iron or oxygen. Mechanistic investigations illustrated the critical role of ·OH, produced from the oxidation of sediment iron, in regulating microbial communities and the chemical sulfide oxidation reaction. Together these results demonstrate that incorporating the advanced FeS oxidation process in sewer sediment enable superior performance of sulfide control at a much lower iron dosage, thereby largely saving chemical use.