This paper seeks to examine the plastic deformation and seismic structural response of a mega-subcontrolled structural system (MSCSS) subjected to strong seismic excitations. Different MSCSS configurations were modeled with nonlinear finite elements, and nonlinear dynamic analyses were performed to examine their behaviors. This paper introduces a novel and optimized MSCSS configuration, configuration 30, which demonstrates remarkable results for the reduction of plastic strain. Utilizing a steel plate shear wall enhances the seismic structural integrity of this system (SPSW). This configuration improved the mean equivalent plastic strain of columns and beams by 51% and 80%, respectively. In addition, a comparison between unstiffened and ring-shaped infill panels of SPSWs demonstrates that ring-shaped infill panels offer greater lateral stiffness and energy dissipation with a 44% reduction in maximum equivalent plastic strain. Compared to configuration 1, configuration 30 exhibited the most controlled structural response, as the minimum residual story drift improvement was 70% in the first, second, and third substructures, respectively, and the maximum coefficient of variation (COV) was 16% and 32% in the acceleration and displacement responses, respectively.