REGEN will pave innovative pathways for the decarbonisation of European neighbourhoods and cities, tackling urgent socioeconomic, climate and built environment challenges by designing a multifaceted Toolbox leveraging cutting-edge digital technologies and life cycle sustainability assessments while engaging citizens and influencing behavioural change. The proposed holistic methodology and framework (Assessment Framework for Urban Regeneration) will validate a catalogue of 50 urban regeneration interventions. This framework will be able to estimate the current revitalisation potential of urban infrastructure, with monitoring using digital twins and evaluation based on sustainability methodologies, facilitating the benchmarking and selection of appropriate intervention strategies. Additionally, the REGEN solutions will be applied with the end-users and all stakeholders in mind, being complemented by social and humanities studies, citizen science, participative design approaches and living labs. The indicators chosen for the assessments will rely on proven life cycle methods, extended to social and economic impacts. This will achieve a holistic sustainability approach, with the end-user being an active participant in the evaluation and validation. REGEN will apply this in 4 demonstration sites where individual buildings, streets and districts are to be constantly monitored for their energy, mobility and circularity. The net benefits of applied interventions will be monitored and assessed on an individual basis. The results will be upscaled at city level, informing key policy orientations already in place and paving the way for broader deployment. An additional 10 virtual regeneration projects will be used to replicate the regeneration interventions and assess their applicability across the EU. This will strengthen the credibility of the interventions catalogue and provide indispensable for knowledge transfer on delivering resilient urban regeneration.