As a hot issue in geological engineering, CO2 flooding and sequestration still face many challenges. Injection of nanoparticles into CO2 can improve the injectability and effective reserves of CO2. However, the migration law of the mixed fluid of CO2 and nanoparticles (NPs-CO2) in the reservoir under the condition of chemical reaction is still unclear. Based on chemical reaction kinetics, a mass transfer model of NPs-CO2 nanofluid in reservoir is established by combining the micro-pore structure change of porous media under CO2-water-rock reactions condition and the migration law of NPs-CO2 fluid. The geochemical reaction process between CO2 and reservoir and the influence of heterogeneity caused by rock microstructure on the miscibility and migration of NPs-CO2 brine fluid are simulated. The results show that the CO2-water-rock reaction increases the heterogeneity of reservoir, and the porosity and permeability are rising as a whole; the increase of reservoir heterogeneity caused by chemical reaction can makes the migration of NPs-CO2 selective. The local accumulation of NPs-CO2 in the unconnected pores will weaken the original oil displacement efficiency to some extent; in the process of CO2 sequestration, the density difference between NPs-CO2 and formation water can not only promote the miscibility of NPs-CO2-brine fluid, but also inhibit the acid fluid under buoyancy. The upward diffusion is moved to the cover layer to prevent the chemical reaction of the rocks in the cap layer, so as ensuring the permanent storage of greenhouse gases.