Accelerating the design and implementation of environmental flows (e-flows) is essential to curb the rapid, ongoing loss of freshwater biodiversity and the benefits it provides to people. However, the effectiveness of e-flow programs may be limited by a singular focus on ensuring adequate flow conditions at local sites, which overlooks the role of other ecological processes. Recent advances in metasystem ecology have shown that biodiversity patterns and ecosystem functions across river networks result from the interplay of local (environmental filtering and biotic interactions) and regional (dispersal) ecological processes. No guidelines currently exist to account for these processes in designing e-flows. We address this gap by providing a step-by-step operational framework that outlines how e-flows can be designed to conserve or restore metasystem dynamics. Our recommendations are relevant to diverse regulatory contexts and can improve e-flow outcomes even in basins with limited in situ data.