The development of efficient heterogeneous persulfate activators is one of the main research topics in the wastewater treatment area. The present work deals with the heterogeneous activation of sodium persulfate (SPS) using nickel oxide/strontium carbonate (NiO/SrCO3) for the degradation of sulfamethoxazole (SMX), a representative compound from the group of antibiotics. Results showed that NiO/SrCO3 exhibited high performance towards the activation of SPS, leading to SMX elimination in brief time spans. The impact of SPS (25–100 mg/L), NiO/SrCO3 (50–250 mg/L), and SMX (0.25–3.00 mg/L) concentration, and initial pH on the decomposition of SMX was further examined. Experiments were also conducted in real matrices such as secondary effluent and bottled water, revealing the existence of retarding phenomena compared to ultrapure water. This behavior was further investigated with the addition of bicarbonates, chlorides, or humic acid in ultrapure water. It was found that organic matter significantly hampered SMX removal. The role of the main radicals (hydroxyl and sulfate radicals) was determined using appropriate radical traps (methanol and tert-butanol). These quenching experiments combined with the conducted electrochemical measurements revealed that both a radical and a non-radical mechanism contribute to the decomposition of SMX.