In recent years, the presence of pharmaceutically active compounds (PhACs) in surface waters and wastewaters has b the effectiveness of conventional water treatment methods. Towards this direction, advanced oxidation processes (AOPs) for the complete elimination of micro pollutants in waters have become an emerging area of research. The present study reports the heterogeneous activation of sodium persulfate (SPS) by LaNiO3 (LNO) perovskite oxide for the degradation of sulfamethoxazole (SMX), an antibiotic agent. LNO was prepared according to a combustion method, and its physicochemical characteristics were identified by means of XRD, BET, TEM, and SEM/EDS. SMX degradation results showed the great efficiency of LNO for SPS activation. Increasing LNO and SPS dosage up to 250 mg/L enhanced the SMX degradation. In contrast, increasing SMX concentration resulted in longer time periods for its degradation. Considering the pH effect, SMX removal was obstructed under basic conditions, while the efficiency was enhanced at near-neutral conditions. The present system’s activity was also tested for piroxicam (PIR) and methylparaben (MeP) degradation, showing promising results. Unfortunately, experiments conducted in real water matrices such as bottled water (BW) and wastewater (WW), showed that SMX removal was limited to less than 25% in both cases. The hindering effects were mainly attributed to bicarbonate ions and organic matter present in aqueous media. The results obtained using suitable radical scavengers revealed the contribution of both hydroxyl and sulfate radicals in degradation reactions. Finally, LNO exhibited good stability under consecutive experimental runs.