Antibiotics have been extensively used as pharmaceuticals for diverse applications. However, their overuse and indiscriminate discharge to water systems have led to increased antibiotic levels in our aquatic environments, which poses risks to human and livestock health. Non-thermal plasma water. However, the issues of process scalability and the mechanisms towards understanding the plasma-induced degradation remain. This study addresses these issues by coupling a non-thermal plasma jet with a continuous flow reactor to reveal the effective mechanisms of amoxicillin degradation. Four industry-relevant feeding gases (nitrogen, air, argon, and oxygen), discharge voltages, and frequencies were assessed. Amoxicillin degradation efficiencies achieved using nitrogen and air were much higher compared to argon and oxygen and further improved by increasing the applied voltage and frequency. The efficiency of plasma-induced degradation depended on the interplay of hydrogen peroxide (H2O2) and nitrite (NO2−), validated by mimicked chemical solutions tests. Insights into prevailing degradation pathways were elucidated through the detection of intermediate products by advanced liquid chromatography-mass spectrometry.