Different pre-conditioning treatments were evaluated in order to stabilize red mud, a waste product from bauxite processing, for obtaining heterogeneous catalysts (named as B1–B3) that can be employed as suitable activators of sodium persulfate (SPS) for the degradation of sulfamethoxazole (SMX), a model antibiotic, in water. The presence of Fe3O4 in the composition of the catalysts was found to be a key factor for a suitable activation of SPS, according to the XPS measurements. The oxidation of SMX was successfully fitted to a pseudo-first-order kinetic model (r2 > 0.96), obtaining a 68% removal after 180 min when 0.8 mg/L of SMX was oxidized with 2 g/L of SPS and 2 g/L of catalyst B3. The presence of organic and/or inorganic constituents in the water matrix significantly hindered the degradation rate of SMX, the apparent kinetic constants being from 2 to 3 times lower than that determined in ultrapure water test. The use of ultrasound irradiation coupled to the addition of B3 catalyst improved importantly the SMX oxidation in real aqueous matrices, thus attaining values of removal which almost triplicated the ones obtained in absence of ultrasounds.