Pharmaceuticals and personal care products (PPCPs) are emerging pollutants that are widespread and raise concerns for the environment and human health. Sulfamethoxazole (SMX), a sulfonamide antibiotic, was the targeted pollutant in this study. The objective was to evaluate the efficiency of the Sono-electro-Fenton technique (SEF) in removing SMX antibiotic using potassium persulfate (K2S2O8) in aqueous solution and compare it with hydrogen peroxide (H2O2). Experiments were conducted under ideal conditions to remove SMX using the SEF technique. Various factors were assessed to determine the optimal conditions for SMX elimination using High-Performance Liquid Chromatography (HPLC) with a constant SMX concentration of 50 mg/l initially. The study determined that specific pH, oxidant dosage, electrolysis time, and voltage settings were crucial for effective removal of the antibiotic using the SEF technique. Iron dissolution and energy consumption were also examined at different voltage levels. The study then tested these optimized conditions with varying initial concentrations of SMX, finding different removal efficiencies between K2S2O8 and H2O2, with H2O2 becoming less efficient as SMX concentrations increased. SMX concentrations were also studied in the presence of ferric chloride hexahydrate (FeCl3.6H2O) using different ratios with K2S2O8 and H2O2. Results showed that using the K2S2O8:FeCl3.6H2O (0.8 mL:0.8 mL) ratio resulted in removal efficiencies of 49%, 77%, 80%, 99%, and 92% for concentrations of 0.5 mg/L, 1 mg/L, 1.5 mg/L, 2 mg/L, and 2.5 mg/L, respectively. Conversely, using the H2O2:FeCl3.6H2O (0.8 mL:0.8 mL) ratio led to 99%, 98%, 94%, 50%, and 50% removal of the pollutant for the same concentrations. The kinetics of SMX removal at different initial concentrations and time intervals were investigated, showing that the reaction followed a pseudo-second-order model. Ultimately, the optimal SMX concentration for achieving higher removal efficiency using the SEF technique with K2S2O8 was found to be 1.5 mg/L.