U.S. experience in offshore wind is limited, and high costs are expected unless innovations are introduced in one or multiple aspects of the project, from the installed technology to the balance of system (BOS). The substructure is the main single component responsible for the BOS capital expenditure (CapEx) and thus one that, if improved, could yield significant levelized cost of energy (LCOE) savings. For projects in U.S. waters, multimember, lattice structures (also known as jackets) can render required stiffness for transitional water depths at potentially lower costs than monopiles (MPs). In this study, we used a systems engineering approach to evaluate the LCOE of prototypical wind power plants at six locations along the eastern seaboard and the Gulf of Mexico for both types of support structures. Using a reference wind turbine and actual metocean conditions for the selected sites, we calculated loads for a parked and an operational situation, and we optimized the MP- and jacket-based support structures to minimize their overall mass. Using a suite of cost models, we then computed their associated LCOE. For all water depths, the MP-based configurations were heavier than their jacket counterparts, but the overall costs for the MPs were less than they were for jackets up to depths of slightly less than 30 m. When the associated manufacturing and installation costs were included, jackets resulted in lower LCOE for depths greater than 40 m. These results can be used by U.S. stakeholders to understand the potential for different technologies at different sites, but the methodology illustrated in this study can be further employed to analyze the effects of innovations and design choices throughout wind power plant systems.