Reliable assessment of the complex natural exchange processes between connected hydrological reservoirs is crucial for estimating hydrological properties, safeguarding ecosystem services, and effectively managing water resources. Although many hydrological or water resource applications require information at a “large scale”, the highly dynamic, seasonal variations of the water discharge and sediment exchange processes between local basins and connected large rivers lead to complex and difficult-to-assess hydrological behaviors in large river-lake systems. This special issue aims to provide the interested reader with some of the latest achievements, experiences gained and challenges addressed related to research in large river-lake systems. Therefore, a diverse group of 15 new articles has been gathered bringing together the cutting-edge research of more than 60 authors on monitoring, modeling, and data science methods for large river-lake systems.