Climate change is an undeniable reality that endangers the integrity of the human and built environment. One component of the built environment that may be particularly threatened by the negative effects of climate change is transportation infrastructure, and particularly road pavement networks. Climate change is expected to impact not only the physical infrastructure but also its owners and managers as well as the long-term operators and users. This study presents the results of a comprehensive life-cycle cost analysis (LCCA) aimed at quantifying the potential economic impacts for road authorities and users, resulting from considering future climate projections in the design of thick flexible pavements, typical for highways and interstates, located in each one of the four climate zones defined in the United States-based Long-Term Pavement Performance (LTPP) program. For that purpose, it adopts a novel approach that uses hourly high-resolution spatial and temporal projections downscaled from a global climate model for the higher RCP8.5 scenario at the scale of individual weather stations for three different current or future climates, (2001–2020, 2041–2060, and 2081–2100) and a baseline period of 1981–2000, as input to the AASHTOWare Pavement ME DesignTM model. Finally, the potential life-cycle economic impact on highway agency and road user costs in four U.S. climate zones are quantified.