This paper presents a System of Systems Engineering approach to aircraft design. For this purpose, conventional design disciplines are coupled with Agent-Based Modeling and Simulation (ABMS) defining a unique optimization problem. The proposed methodology is applied to design seaplanes for an on-demand transportation system connecting the Greek islands. Within this network, diverse scenarios are analyzed by varying parameters of the model such as fleet size and travel demands at each seaport. The objective is to show the impact of including ABMS in the design workflow on the optimized seaplane design parameters. The optimum designs are evaluated on the basis of a number of classic performance metrics, to assess to what extent they can represent a competitive alternative to existent maritime means of transportation. The results reveal optimal fleet performance for seaplanes characterized by lower cruise speeds and passenger capacities, as compared to those derived from conventional methodologies and to existing designs.