Microbial desalination cell (MDC) offers a new and sustainable approach to desalinate saltwater by directly utilizing the electrical power generated by bacteria during organic matter oxidation. The successful MDC development relies on the fundamental understanding of the interactions and removal mechanisms of different ion species present in saline water or wastewater, but there is limited understanding of ion transport mechanisms in MDCs and potential membrane fouling/scaling during treatment of wastewater and saline water. In this study, we investigated the transport behavior of multiple ions in MDCs and the effects of ionic composition on system performance and membrane scaling and fouling. The results showed that the presence of sparingly soluble cations in saltwater negatively affected MDC power generation and desalination. Membrane characterization revealed that the majority of such ions precipitated on the ion exchange membrane surface and caused membrane scaling. Anions such as Br− and SO42− with Na+ as counter-ion did not show significant effects on system performance. Sharp pH changes were observed during MDC operation, which resulted in the inhibited MDC anode microbial activity and the accelerated formation of alkaline precipitations on both sides of the cation exchange membrane. An anode–cathode recirculation approach was proved to be effective to solve such problems and improved the desalination rate by 152% and the electron harvest rate by 98%.