Based on the existing experimental investigation on RC frame with a column removal, the three-dimensional finite element simulation with a combination of separated and integral models for a four-story two-span RC frame structure was established by using the finite element software AUTODYN, and analyzed through three stages. The effect of gas-solid interaction was considered to simulate the dynamic response and failure modes of RC frame due to the removal of reinforced concrete columns under explosion loads. In the numerical simulation, the strain rate effects were also taken into account for the dynamical constitutive behaviors of the materials. In the case of the failure of the corner column or the short side column under blast loads, the failure modes of the column and the dynamic displacement of the beam-column joints from FE models agreed well with the experimental results. Meanwhile, the failure process of the column removal and the influence of the longitudinal-steel in the column on the dynamic response of the RC frame structure were examined. Moreover, the simulation results indicate that the way adopting separated and integral models in the plastic and elastic deformation region, respectively, not only ensured the authenticity and adaptiveness of the simulation of the RC frame under column removal, but also reduced substantial computational effort. Therefore, this developed model can provide a reference for the further studies on the parametric analysis and collapse mode control of RC frame structures under blast loads.