Large-span structures are essential for various applications, including commercial buildings, train stations, ferry-boat stations, and airports. However, constructing such structures in seismic areas requires the use of a considerable amount of structural materials, resulting in high resource consumption and CO2 emissions. To overcome this problem, a sustainable design strategy for large-span structures in seismic areas using form finding and structural optimization tools is here proposed, starting from a previous work by some of the authors. This strategy is employed for designing an optimized innovative hybrid structural system comprising of a concrete shell coupled with suspended steel multi-floor frame system. The shape of the shell is initially determined by a form finding procedure for different plan forms; a linear finite element analysis under static and dynamic loads allows to select the most performing shell shape in terms of stress and deformation levels. The framed system is then suspended from the selected shell, and the structural layout is optimized by a shell thickness optimization conducted for gravitational loads. The whole structural system, optimized for gravitational loads, reveals efficient performance also under significant seismic actions, indicating a beneficial interaction between the shell and the frame structure. Therefore, the innovative hybrid structural system and the design approach here proposed helps reduce the quantity of structural material usage, minimizing environmental impact and enhancing structural efficiency.