The present study, based a tip-to-plane pulsed corona setup, examined the effects of tip-water distance, radius of curvature of electrode tip, and pulse voltage on the production of liquid-phase RONS used an indicator of degradation performance. Measurements of long-lived RONS species (nitrates, nitrites and H2O2) in deionized water were specifically analyzed. The optimum conditions were used for the removal of a high concentration (500 mg/L) of 4-acetaminophen (i.e. paracetamol) with study of oxidation by-products and their toxicity. The results showed that optimum RONS production in the liquid phase occurred for a short gap distance (4 mm), a tip curvature radius of 100 μm and a pulsed voltage of 10 kV and 10 kHz corresponding to an energetic corona spark regime which is characterized by optical emission spectroscopic measurements. Using these optimal corona discharge parameters, the study showed that after 30 min of exposure to the air plasma, 60 % removal efficiency was achieved at an initial paracetamol concentration of 500 mg/L based on HPLC-DAD sample analysis. GC–MS and LC-MS analysis of treated samples enabled us to identify and characterize two new by-products not previously identified in the literature: N-(4-(4-hydroxyphenylamino) phenyl) acetamide (m/z: 242) and N-(4-aminophenyl) acetamide (m/z: 150), most of which were nitrogen compounds. Further analysis of the toxicity of these by-products to the human cell line (HEK-293) demonstrated that the treated water was not toxic. Overall, these results show that the CDP system is one of the best techniques for treating highly polluted wastewater.