<p>With the growing population, it is critical for everyone to practice sustainable development in order to conserve resources for future generations. Different approaches to bioenergy generation and water treatment should be considered, which have sparked interest in the field of microbial fuel cells (MFCs). Previous research has primarily focused on parameter variation to improve the performance of MFCs. However, this study focuses solely on the optimization of these parameters as well as their interactions, mainly using tannery wastewater and cow dung as microbial inoculum. The effects of operating parameters such as pH, electrode spacing, and external resistance on power density and chemical oxygen demand (COD) removal were studied using response surface methodology (RSM). Maximum power production (200.586&#xa0;mW/m²) and COD removal (82.674%) were obtained under neutral pH conditions with an electrode spacing of 1&#xa0;cm and an external resistance of 2.664&#xa0;Ωm² (1800&#xa0;Ω). A system with optimized RSM parameters resulted in better power production, COD removal, Coulombic efficiency (CE), and normalized energy recovery (NER) than the non-optimized system, with a CE and NER value 5.9 and 3.4 times higher than the non-optimized system, respectively. This indicates that optimized MFCs efficiently convert organic compounds in wastewater to electricity. Based on the findings of this study, the maximum MFC performance for a scaled-up system can be determined as the study provides a basic understanding of the interactions between all these parameters.</p> Graphical abstract <p></p>