As the control brain of the petrochemical plant, blast-resistant performance requirements are important for the sustainability of the petrochemical control room and should be guaranteed when the vapor cloud explosion occurs in the petrochemical production process. The 3D-Kagome truss core sandwich structure is a kind of blast-resistant material with high energy absorption and recycling. Considering the influential factors of the radius of the truss core rod and thickness of the upper and lower panels, in this paper, the blast-resistant performance of a real steel petrochemical control room with a 3D-Kagome truss core sandwich wall was analyzed. With the optimization goal of plastic deformation energy and panel displacement, the optimal wall thickness and radius of the truss core rod were obtained. The optimized blast-resistant walls were assembled, and the dynamic response of the steel petrochemical control room with the 3D-Kagome truss core sandwich blast-resistant wall was analyzed. The simulation results indicate that the truss core layer is ineffective in dissipating blast energy when the radius ratio of the truss core rod exceeds 2.7% of the total wall thickness. Moreover, as the thickness of the upper and lower panels increases from 0.5 cm to 3 cm, the proportion of plastic deformation energy in the truss core layer gradually rises from 55% to 95%, stabilizing at around 90%. The optimal configuration for blast resistance is achieved when the panel thickness ratio is 6.7% of the total wall thickness; the truss core rod radius ratio is 2.7% of the total thickness. This study establishes the effectiveness of the optimized 3D-Kagome sandwich wall as a blast-resistant solution for steel petrochemical control rooms.