Abstract: Reinforced Concrete (RC) frame structures play a key role in numerous political and economic activities. However, the increasing frequency of explosion attacks and public safety incidents, coupled with the complex international situation, has rendered RC frame structures as crucial targets for both attack and protection. To investigate the damage effects of multiple explosions on RC frame structures, a full-scale two-story RC frame structure with masonry walls was designed and constructed. Based on this building, external and internal explosion tests were conducted under different TNT equivalents (11.573kg and 20kg). The load characteristics of shock waves, dynamic response and failure modes of structural components were examined. The results show that under close-range external explosion, the floor slabs and masonry walls can attenuate the shock wave loads propagated into the adjacent room, with a peak overpressure reduction of 84.75%. The floor slabs and masonry walls exhibit local shear failure, while the damage to the internal components and the global structure is minor. In contrast, under internal explosion, the floor slabs and masonry walls show global shear failure, with higher damage compared to the RC columns and beams. In addition to the shock wave loads, the explosive ejection of wall/slab fragments from the explosion source room is the primary reason for damage to the masonry walls and slabs along the direction of shock wave propagation. Finally, based on damage assessment criteria, the damage levels of components, rooms, and the RC structure for each test were determined. The damage level and range of RC structure under internal explosion is significantly higher than that under external explosion loads.