Amine processes are the advanced technology available today for the removal of carbon dioxide (CO2) and hydrogen sulfide (H2S) acid gases. Methyldiethanolamine (MDEA) is a well-known tertiary amine used selectively for the removal of carbon dioxide from natural gas. There are many parameters that can affect the efficiency of separating these acid gases from natural gas. In this paper, we have studied, modeled, and optimized different operating parameters of sour gas feed and MDEA solution which affect the CO2 recovery efficiency from an existing sweetening unit. These operating parameters are the sour gas feed temperature and pressure, volume ratio (%) of carbon dioxide in the feed gas, amine inlet temperature, and amine circulation rate. Actual data were collected from an industrial CO2 sweetening unit over one year. These data were used to study the effect of the studied operating parameters on the recovery efficiency of CO2 from the sweetening unit. All studied operating parameters were found to have an impact on the recovery efficiency of the removed gases. A response surface methodology approach was used in Design-Expert software version 13 to model the relationship between considered operating parameters and CO2 recovery efficiency. In addition, Design Expert numerical optimization has been used to maximize CO2 recovery efficiency. The results showed that the optimal range of sour gas feed temperature is 34.71 to 45.56 °C, sour gas feed pressure is 8.32 to 10.04 barg, the volume ratio (%) of carbon dioxide in the sour gas feed is 8.51 to 10.15, the temperature of the amine is 38.03 to 43.96 °C, and the amine circulation rate is 788.39 to 1122.35 m3/h. The presented work can be considered as a guideline for increasing the recovery efficiency of CO2 for both new and existing sweetening units.