This paper presents a mechanism and method for simulating the axial–shear–bending interaction of a reinforced concrete (RC) column. The three-dimensional model of a multi-story infilled RC frame was modeled using the OpenSees software. Static pushover and nonlinear dynamic analyses under fortification and rare earthquakes were conducted using the model. Finally, based on the incremental dynamic analyses of 22 suites of ground-motion records, the global collapse resistance capacity of the infilled RC frame was evaluated using the evaluation method of a normal distribution. The analytical results show that the axial–shear–bending interaction is a key factor that affects the seismic response of infilled RC frames. Under the fortification earthquake condition, no obvious damage to physical structures was evident; the influence was relatively minor. However, under the condition of a rare earthquake, severe damage to physical structures was evident, resulting in the underestimation of the lateral inter-story drift ratio, while the degradation rates of the load capacity and global collapse resistance capacities for the infilled concrete frames were highly overestimated when the axial–shear–bending interaction was not considered.