In this paper, a cold plasma process was employed for the removal of amoxicillin (AM) and total organic carbon (TOC) from real hospital wastewater in Vietnam via the statistical design of a central composite design (CCD), with three factors of initial pH, applied voltage, and reaction time, respectively. Under optimal treatment conditions of a reaction time of 36.5 min, initial pH of 10.5, and an applied voltage of 36.5 kV, a good TOC removal efficiency of ~72.4% as well as most of the amoxicillin was eliminated. In addition, theoretical approaches (e.g., DFT and NBO calculations) revealed the proposed major degradation pathways of AM and the final mineralization to H₂O, CO₂, SO₄ ²⁻, and NO₃⁻. The obtained results demonstrate the potential of employing a cold plasma process for the treatment of pharmaceutical-containing wastewater.