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Regional-scale ecological processes, such as the spatial flows of material, energy, and organisms, are fundamental for maintaining biodiversity and ecosystem functioning in river networks. Yet these processes remain largely overlooked in most river management practices and underlying policies. Here, we propose adoption of a meta-system approach, where regional processes acting at different levels of ecological organization – populations, communities, and ecosystems – are integrated into conventional river conservation, restoration, and biomonitoring. We also describe a series of measurements and indicators that could be assimilated into the implementation of relevant biodiversity and environmental policies. Finally, we highlight the need for alternative management strategies that can guide practitioners toward applying recent advances in ecology to preserve and restore river ecosystems and the ecosystem services they provide, in the context of increasing alteration of river network connectivity worldwide. In a nutshell: • Rivers are hotspots of biodiversity and provide essential ecosystem functions and services, but face numerous threats globally • Understanding of how rivers are organized across spatial scales has progressed considerably over the past several decades, proving that regional-scale processes are vital for preserving population, community, and ecosystem dynamics • However, most existing river conservation, restoration, and biomonitoring practices focus on local-scale strategies and measures • To improve the management of river networks in the Anthropocene, we suggest additional metrics and assessment approaches that incorporate regional processes more effectively