In this article, the Dimethyl Carbonate (DMC) synthesis process was investigated thermodynamically based on a well-optimized DMC system for a developed configuration, according to a real industrial plant, presented by Huang et al. Exergy analysis was performed using ProSimPlus software as an efficient process modeling and simulation environment that is uniquely capable of exergy balance computations. The key operational variables such as the reflux ratio (Rr), feed temperatures, and feed tray location were varied to explore their impact on the total irreversibilities, global intrinsic efficiency, and DMC purity. The influence of the high pressure (HP) column reflux ratio was the most effective parameter on the exergy destruction and DMC purity, which also significantly increased the duties of the HP column reboiler and condenser. The steady state results are reported in comparison with those found in the literature, and an excellent match is shown between them.