The process of amine sweetening of natural gas is crucial to purify it, meet environmental regulations, and boost its commercial value. This study proposes a novel hybrid optimization framework combining Response Surface Methodology (RSM) with process simulation, specifically addressing additive impacts on MDEA-based solvents, a combination not extensively explored in prior studies. The research recommends a new combination of response surface methodology (RSM) and process simulation to address this goal. Using RSM for optimization is a statistical technique applied to model the functional relationship between major input variables (like temperature, pressure, concentration of additives, and MDEA). Therefore, integrating RSM with process simulation helps assess scenarios that give reliable results. In particular, this study considers how additives affect indicators such as acid gas removal efficiencies (CO2 and H2S), energy consumption, percent of yield for solvent regeneration, and overall economy. A framework for optimizing acid gas removal efficiency has been developed by systematically varying the concentrations of additives across specific predefined ranges so that optimal operating conditions are determined that maximize both acid gas removal efficiency and yield of solvent regeneration while minimizing utility consumption, resulting in low total annual costs. The results show that incorporating additives into MDEA-based solvents significantly promotes acid gas removal efficiency at reduced energy consumption. Additionally, it has been noted that some additives have cooperative effects when used with MDEA, leading to enhanced solvent regeneration yield and lowered total annual cost. These findings underscore the significant economic benefits of our proposed methodology, which can lend valuable insights to plant operators and engineers who wish to optimize their amine-sweetening processes. The study's findings highlight the substantial financial benefits that can be derived from the addition of blending agents into MDEA-based solvents, thus enhancing processing efficiencies and making them economically viable in the natural gas industry.