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Thermo‐hydro‐mechanical‐chemical (THMC) interactions are prevalent during CO2 geological sequestration (CGS). In this study, a sequential coupling THMC numerical simulation program was constructed, which can be used to explore the following issues of CGS: fluid and heat flow, solute transport; stresses, displacements and rock failures related to geo‐mechanical effects; equilibrium and kinetic chemical reactions; chemical damage to mechanical properties of the rock. Then, the coupling program was applied to the Ordos CGS Project to study the formation response under the multi‐field interaction caused by CO2 injection. The simulation results show that the mechanical process dominates the short CO2 injection period. Specifically, the formation's permeability near the injection well increases by 43%, due to the reduction of effective stress, which significantly promotes the lateral migration of CO2. When the injection rate exceeds 0.15 million tons per year, the cohesion of the reservoir rock is not enough to resist the shear force inside the rock and rock failure may occur. During the subsequent long‐term sequestration period (200 years), the influence of mineral reactions gradually increases. Due to calcite dissolution, the shear modulus of caprock is predicted to decrease by 7.6%, which will to some extent increase the risk of rock failure. [ABSTRACT FROM AUTHOR]