<p>In this research, the parameters of the electrochemical advanced oxidation process using a graphite substrate lead dioxide (GSLD) electrode were optimized by Box Behnken design-response surface methodology (BBD-RSM) for the elimination of ciprofloxacin (CIP). The optimized system (pH: 3.18, applied current: 492&#xa0;mA, electrode spacing: 2&#xa0;cm, electrolyte concentration: 0.14&#xa0;M, and treatment duration: 77&#xa0;min) equipped with a graphite substrate lead dioxide anode can effectively eliminate CIP, a highly persistent antibiotic associated with antimicrobial resistance, from water matrices. Achieving 90% removal at a low energy requirement (6.64 kWh m^− 3) highlights its efficiency and makes it a more economical alternative to many existing advanced oxidation processes. The Pareto chart indicated that the solution’s pH was the primary contributing factor, accounting for 45% of the total effect across all parameters. Further using these optimized values, the process removed nearly 70% of CIP from municipal wastewater, despite the presence of natural organic matter and competing ions, which further demonstrates its suitability for real environmental applications. The increment in biodegradability from 0.32 to 0.56 after treatment suggests that the treated water becomes more amenable to subsequent biological treatment processes. The degradation byproducts due to the partial mineralization were identified, and the mechanism of ciprofloxacin degradation by three different pathways was evaluated. Overall, the findings confirm that the optimized process offered a practical, scalable, and effective solution for treating antibiotic-contaminated wastewater under real-world conditions.</p> Graphical Abstract <p></p>