AbstractBACKGROUNDMicrobial desalination cell (MDC) is a new technology in the use of electrical energy for water desalination and wastewater treatment.RESULTSOpen circuit (OC) and closed circuit (CC) modes were successfully simulated with initial TDS concentrations of 10 g/L and 10–15 g/L, respectively (an external resistance of only 150 Ω was applied for CC). After 160 h of operation, the maximum OC voltage, desalination efficiency and COD removal efficiency were 809 mV, 32.2% and 79.2%, respectively. The maximum voltage was also obtained when the external resistances were 150 Ω (423.4 and 438 mV) for the initial NaCl concentrations (10 and 15 g/L) in the central chamber, respectively. Moreover, the maximal desalting and COD removal efficiencies after 24 h run‐time were (30% and 28%) and (24% and 25%) for initial NaCl concentrations (10 or 15 g/L) in the central chamber, respectively. Maintaining pH (8.61, 7.01) to (7.85, 7.8) in anode and cathode chambers was studied. This research accurately depicted microbial desalination's efficiency in generating OC voltages and CC electrical energy via Box–Behnken Design Distribution (BBD). Investigated factors’ interactions (initial salt/COD concentrations, time) on CC system's energy efficiency. Resulted in peak productivity at (1.85 mW), OC reaching (1100 mV).CONCLUSIONFinally, the research paper gave exciting results in improving the efficiency of the microbial desalination cell to increase the ability to produce electrical energy and desalinate water. © 2023 Society of Chemical Industry (SCI).