Hydro-climatic changes and the increasing release of pollutants into rivers by human activities tend to affect the quality of watercourses, to alter aquatic ecosystems and to reduce the amount of useable water. The ecological and chemical states of rivers and their evolution is thus of growing concern. In Europe and Switzerland, water policies are progressively shifting towards a holistic approach of river systems. The European Commission notably established a framework to highlight rivers’ ecological deficits and to enhance regional or local water management plans. In Switzerland, a similar framework is currently under development. In this paper, both procedures are compared and implemented in a Swiss catchment dominated by agricultural activities. The aim is to define the challenges that still need to be addressed to assess and sustain river health. The hydromorphological, ecological, and ecotoxicological quality of the river was evaluated. Both frameworks highlighted the fact that no section of the river can currently be classified as being in a good environmental state and that the state deteriorates as tributaries and wastewater discharge flow into the main riverbed. Chemical issues and water quality changes due to hydro-climatic variations and management strategies were also pinpointed. Both frameworks are thus useful tools to survey changes in rivers quality in space and over time. However, challenges remain regarding the appropriate strategies to monitor and analyze chemicals, the definition of target values and conditions, the evaluation and integration of human-induced pressures, and the overall evaluation of the state of a river. The development of integrated indicators or of ecosystem services approaches is considered as a potential solution to explore river health and to define efficient restoration measures by water managers.