Natural gas hydrate (NGH) is a solid clathrate compound formed by water and natural gas at low temperatures and high pressures characterized by abundant resources and a wide distribution. The depressurization-assisted CO 2 replacement method has the advantage of concurrently producing CH 4 while sequestering CO 2 , rendering a promising approach for exploiting NGH. Some experiments have been conducted on depressurization-assisted CO 2 replacement. However, a comparative analysis of the depressurization and CO 2 replacement application sequences remains ambiguous. In this study, a numerical model for depressurization-assisted CO 2 replacement was established to clarify the application sequences, analyze the influence of different factors, and propose the optimal production scheme based on the optimization algorithm. Results indicated that the formation of the CO 2 hydrate promoted the dissociation of the CH 4 hydrate. Depressurization, followed by CO 2 replacement represented the optimal production sequence, with cumulative gas production (V p ) and CO 2 sequestration ratios (R CO2 ) higher than those of CO 2 replacement, followed by depressurization by 3.17 and 1.61%, respectively. As the production pressure decreased from 7 to 3 MPa, both V p and R CO2 increased. The CO 2 injection rate had little effect on V p but affected R CO2 , while the CO 2 injection temperature had less effect on any of them. According to the particle swarm optimization algorithm (PSO) results, the optimal scheme was a bottom hole pressure of 3 MPa, a CO 2 injection rate of 7000 m 3 /d, a CO 2 injection temperature of 22 °C, and a production and injection well spacing of 280 m. This study provides insights into the potential applications of depressurization-assisted CO 2 replacement in the field tests of hydrate production.