The threat of blasts has a devastating effect on vehicles, buildings, and even human lives, creating a pressing need for the development of blast protection systems. A novel multi-layered kirigami corrugated (MKC) sandwich panel has been proposed, featuring kirigami corrugated cores with different geometries in layers while maintaining the same mass, to investigate its blast-resistance performance. The dynamic response of MKC sandwich panels in seven configurations subjected to blast loading was numerically studied via finite element simulations, with their dynamic deformation evolution, deformation/failure modes, panel deflections, and core compression systematically analyzed. The results indicate that the dynamic deformation process of MKC sandwich panels can be approximately decoupled into four stages. The deformation and failure modes of the panels and the formation of plastic hinges in each part of the cell were further analyzed. Moreover, rear panel deflections are found to be significantly influenced by the multi-layer arrangement of the structure. Compared with the original configuration, adjusting the core layer configuration could reduce the peak deflection by 41 %, indicating the ability of multi-layer design to regulate the structural blast resistance. Designing the core at the rear side to be stronger significantly improves the structure’s blast resistance. Subsequently, the response of MKC sandwich panels was modeled using a surrogate modeling technique, with its model accuracy validated. A high-efficiency optimization procedure factoring structural deformation resistance and energy absorption performance of the MKC sandwich panels was proposed by coupling the surrogate model with the NSGA-II algorithm. The optimal sandwich panel has a reduced rear panel peak deformation by up to 55.7 % while increasing specific energy absorption by approximately 15.8 % compared with the preliminary design. This optimized core layer arrangement strategy can significantly enhance the performance of multi-layer structures, while ensuring the convenience of fabrication and improving the material utilization efficiency.