River networks are among Earth’s most threatened hot-spots of biodiversity and provide key ecosystem services (e.g., supply drinking water and food, climate regulation) essential to sustaining human well-being. Climate change and increased human water use are causing more rivers and streams to dry, with devastating impacts on biodiversity and ecosystem services. Currently, more than a half of the global river networks consist of drying channels, and these are expanding dramatically. However, drying river networks (DRNs) have received little attention from scientists and policy makers, and the public is unaware of their importance. Consequently, there is no effective integrated biodiversity conservation or ecosystem management strategy of DRNs. A multidisciplinary team of 25 experts from 11 countries in Europe, South America, China and the USA will build on EU efforts to assess the cascading effects of climate change on biodiversity, ecosystem functions and ecosystem services of DRNs through changes in flow regimes and water use. DRYvER (DRYing riVER networks) will gather and upscale empirical and modelling data from nine focal DRNs (case studies) in Europe (EU) and Community of Latin American and Caribbean States (CELAC) to develop a meta-system framework applicable to Europe and worldwide. It will also generate crucial knowledge-based strategies, tools and guidelines for economically-efficient adaptive management of DRNs. Working closely with stakeholders and end-users, DRYvER will co-develop strategies to mitigate and adapt to climate change impacts in DRNs, integrating hydrological, ecological (including nature-based solutions), socio-economic and policy perspectives. The end results of DRYvER will contribute to reaching the objectives of the Paris Agreement and placing Europe at the forefront of research on climate change.