The main objective of this research is to describe a multidisciplinary investigation part of an ongoing research project. The contribution focuses on the identification and selection of innovative technologies and operative methodologies capable of fostering the sustainable innovation and resilience of the Italian N-E territory by addressing four challenges: energy transition, environmental challenges, adaptation to climate change, and digitalisation. The investigation devised an original conceptual research framework aiming to identify possible solutions and drawing a connection between them and the challenges, by considering the actions, the technological and methodological support, and, indirectly, the European and global policy objectives they help to reach. The research results are: (i) a definition of the four challenges in light of the built environment and construction sector; (ii) the conceptual research framework schema as a replicable instrument; (iii) its contextualization to the research scope; (iv) a preliminary list of technologies and methodologies supporting the sustainable innovation in the given territorial context; and (v) a ranking of the most promising solutions according to their effectiveness and application potential. The results highlight how, in the Italian N-E context, the solutions most effective in delivering sustainability and resilience are the ones operating in the built environment by preserving the built resources, mainly by addressing the building envelope and structure.