The worsening effects of climate change in urban settings imply the application of effective measures for climate adaptation and mitigation actions on the building–open space system. It means the development of innovative climate-resilient design approaches through the elaboration of knowledge processes and methodological workflows supported by key enabling technologies (KETs). This paper presents the middle results of the research project PRIN (Progetti di Rilevante Interesse Nazionale) 2017 “TECH-START—key enabling TECHnologies and Smart environmenT in the Age of gReen economy. Convergent innovations in the open space/building system for climaTe mitigation”. The goal of this paper is to show a methodological workflow and an operational protocol for digital modeling and simulation for the evaluation of climate adaptation and mitigation strategies in urban settings, applied to the case of the former Centro Polifunzionale Marianella in the northern area of Naples. The results of the experimental application demonstrate the effectiveness of the meta-design proposals, with particular reference to the reduction of vulnerability to the heat wave phenomenon. The experimentation expresses the consistency of the methodological workflow. The results obtained demonstrate that the methodological approach based on KETs is effective in the evaluation of climate-resilient design actions through the definition of a set of indicators whose values return performance and characteristics of the design solutions.