Acid gas absorption using amine solution is a common method for large-scale acid gas separation, although this separation technique suffers from high energy requirements. In this study, the amine-based acid gas removal (AGR) unit aims for operation enhancement. The new amine mixture, a combination of MDEA-DEA-PZ, is used to remove acid gas components from natural gas. As energy consumption is of high importance for both the industry and community, a systematic exergoeconomic optimization and a sensitivity analysis are performed to avoid production loss and enhance the AGR unit's energy efficiency. An exergy assessment is performed to determine the irreversibility and exergy efficiency of the AGR equipment. The stripper and absorber columns show the largest exergy destruction, that is 8.48 and 7.93 MW, respectively; almost 80% of the entire exergy destruction belongs to the stripper and absorber. The exergoeconomic parameters, such as relative cost difference, exergoeconomic factor, and most importantly, the exergy destruction cost, are determined for the key equipment of the AGR unit. The stripper accounts for the largest exergy destruction cost (0.5260 $/s), followed by the absorber (0.2950 $/s). The Taguchi approach is employed to conduct a proper sensitivity analysis and to determine the optimal operation state with the lowest total exergy destruction cost. Five key parameters, including stripper pressure, lean amine loading, lean amine temperature, lean amine concentration, and PZ concentration, are selected for the optimization phase. It is concluded that the stripper pressure and lean amine loading (with 28 and 25% relative significance, respectively) are the key factors with the largest shares in the total exergy destruction value. The optimal operation state obtained by the Taguchi method shows a remarkable reduction in the exergy destruction cost (19.32%) and steam consumption (23.88%). According to the environmental assessment, CO 2 emissions mitigate from 118.88 to 90.49 t/d while operating the process at the optimal conditions. In addition, the carbon tax is reduced to almost 23% at the optimal condition, and the steam cost declines from 3.77 × 10 6 to 2.87 × 10 6 USD/year. This study further highlights the importance of exergoeconomic assessment as a useful strategy for determining the irreversibility costs in energy and chemical sectors.