The ubiquitous natural sedimentary reservoirs and their high permeability have made the CO2 plume geothermal system increasingly attractive. However, the complicated fluid-rock interactions during the geothermal exploitation can cause severe reservoir damage, constraining the excellent heat mining performance of the CO2 and decreasing the possible applications of the CO2 plume geothermal system. In order to analyze and solve this energy issue affecting the geothermal exploitation, in this study, a comprehensive numerical simulation model was established, which can consider formation water evaporation, salt precipitation, CO2-water-rock geochemical reactions, and the changes in reservoir porosity and permeability in the CO2 plume geothermal (CPG) system. Using this model, the geochemical reactions and salt precipitation and their effects on the geothermal exploitation were analyzed, and some measures were proposed to reduce the influence of fluid-rock interactions on the heat mining rate. The simulation results show that the gravity and the negative gas-liquid capillary pressure gradient induced by evaporation can cause the formation water to flow toward the injector. The back flow of the formation water results in salt precipitation accumulation in the injection well region, which can cause severe reservoir damage and consequent reductions to the heat mining rate. The CO2-water-rock geochemical reactions could result in the dissolution of certain minerals and precipitation of others, but its minimal influence on the heat mining rate can be ignored. However, salt precipitation can affect the geochemical reactions by influencing the CO2 flow and distribution, which can reduce the heat mining rate up to 2/5 of the original. Sensitivity studies show that the reservoir condition can affect the salt precipitation and heat mining rate, so a sedimentary reservoir with high temperature, high porosity and permeability, and low salinity should be selected for CPG application, with an appropriately high injection-production pressure difference. The injection of low salinity water before CO2 injection and the combined injection of CO2 and water vapor can be applied to reduce the salt precipitation and increase the heat mining rate in the CPG system.