The transition from lab-scale studies to pilot-scale applications is a critical step in advancing water remediation technologies. While laboratory experiments provide valuable insights into the underlying mechanisms and method effectiveness, pilot-scale studies are essential for evaluating their practical feasibility and scalability. This progression addresses challenges related to operational conditions, effectiveness and energy requirements in real-world scenarios. In this study, the potential of nanopulsed plasma bubbles, when scaled up from a lab environment, was explored by investigating critical experimental parameters, such as plasma gas, pulse voltage, and pulse repetition rate, while also analyzing plasma-treated water composition. To validate the broad effectiveness of this method, various classes of highly toxic organic pollutants were examined in terms of pollutant degradation efficiency and energy requirements. The pilot-scale plasma bubble reactor generated a high concentration of short-lived reactive species with minimal production of long-lived species. Additionally, successful degradation of all pollutants was achieved in both lab- and pilot-scale setups, with even lower electrical energy-per-order (EEO) values at the pilot scale, 2–3 orders of magnitude lower compared to other advanced oxidation processes. This study aimed to bridge the gap between lab-scale plasma bubbles and upscaled systems, supporting the rapid, effective, and energy-efficient destruction of organic pollutants in water.