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The adoption of Nature-Based Solutions (NBSs) represents a novel means to mitigate natural hazards. In the framework of the OPERANDUM project, this study introduces a methodology to assess the efficiency of the NBSs and a series of Open-Air Laboratories (OALs) regarded as a proof-of-concept for the wider uptake of NBSs. The OALs are located in Finland, Greece, UK, Italy, and Ireland. The methodology is based on a wide modeling activity, incorporated in the context of future climate scenarios. Herein, we present a series of models’ chains able to estimate the efficiency of the NBSs. While the presented models are mainly well-established, their coupling represents a first fundamental step in the study of the long-term efficacy and impact of the NBSs. In the selected sites, NBSs are utilized to cope with distinct natural hazards: floods, droughts, landslides, salt intrusion, and nutrient and sediment loading. The study of the efficacy of NBSs to mitigate these hazards belongs to a series of works devoted to the implementation of NBSs for environmental purposes. Our findings prove that land management plays a crucial role in the process. Specifically, the selected NBSs include intensive forestry; the conversion of urban areas to grassland; dunes; marine seagrass; water retention ponds; live cribwalls; and high-density plantations of woody vegetation and deep-rooted herbaceous vegetation. The management of natural resources should eventually consider the effect of NBSs on urban and rural areas, as their employment is becoming widespread.