Effective management of future regional climate risks in interconnected multi-sectoral systems is complicated by uncertainties in risk drivers within both human and natural systems. Comprehensive yet comprehensible targeted climate risk information exploring these uncertainties is essential for the strategic allocation of limited resources to vulnerable areas and sectors in the region. Yet conventional approaches struggle to provide it. This study addresses this gap by introducing an interdisciplinary framework incorporating meteorological, hydrological, and socio-economic perspectives. A “plausibilistic” flood risk assessment approach is presented which combines both climate and socio-economic storylines. Plausible climate scenario storylines are sampled based on their relevance for local impacts, allowing the assessment of conditional changes in high-impact probabilistic discharges. Plausible socio-economic storylines are integrated to asses future urban area and economic sectoral development. This information allows the projection of the impact potential in the region and its cascading socio-economic effects. An example application to the flood-prone, transboundary Lielupe basin shared by Latvia and Lithuania highlights sub-catchments and sectors consistently vulnerable across diverse, relevant, and credible set of future storylines. The framework thus equips regional risk managers with targeted and robust risk information, providing a strong knowledge base for prioritizing adaptation planning.