Reinforced concrete shear wall structures (RCSWs) are commonly used as explosion-resistant chambers for storing hazardous chemical materials and housing high-pressure reaction equipment, serving to isolate blast waves and prevent chain reactions. In this study, full-scale experiments and numerical simulations were conducted to investigate the blast resistance of RC shear wall protective structures subjected to internal explosions. A full-scale RC shear wall structure measuring 9.7 m × 8 m × 6.95 m with a wall thickness of 0.8 m was constructed, and an internal detonation equivalent to 200 kg of TNT was initiated to simulate the extreme loading conditions that may occur in explosion control chambers. Based on experimental data analysis and numerical simulation results, the damage mechanisms and dynamic response characteristics of the structure were clarified. The results indicate that under internal explosions, severe damage first occurs at the wall–joint regions, primarily exhibiting through-thickness shear cracking near the supports. The structural damage process can be divided into two stages: local response and global response. Using validated finite element models, a parametric study was carried out to determine the influence of TNT charge weight and reinforcement configuration on the structural dynamic response. The findings of this research provide theoretical references for the design and strengthening of blast-resistant structures.