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Abstract Background Large-river decision-makers are charged with maintaining diverse ecosystem services through unprecedented social-ecological transformations as climate change and other global stressors intensify. The interconnected, dendritic habitats of rivers, which often demarcate jurisdictional boundaries, generate complex management challenges. Here, we explore how the Resist–Accept–Direct (RAD) framework may enhance large-river management by promoting coordinated and deliberate responses to social-ecological trajectories of change. The RAD framework identifies the full decision space of potential management approaches, wherein managers may resist change to maintain historical conditions, accept change toward different conditions, or direct change to a specified future with novel conditions. In the Upper Mississippi River System, managers are facing social-ecological transformations from more frequent and extreme high-water events. We illustrate how RAD-informed basin-, reach-, and site-scale decisions could: (1) provide cross-spatial scale framing; (2) open the entire decision space of potential management approaches; and (3) enhance coordinated inter-jurisdictional management in response to the trajectory of the Upper Mississippi River hydrograph. Results The RAD framework helps identify plausible long-term trajectories in different reaches (or subbasins) of the river and how the associated social-ecological transformations could be managed by altering site-scale conditions. Strategic reach-scale objectives may reprioritize how, where, and when site conditions could be altered to contribute to the basin goal, given the basin’s plausible trajectories of change (e.g., by coordinating action across sites to alter habitat connectivity, diversity, and redundancy in the river mosaic). Conclusions When faced with long-term systemic transformations (e.g., > 50 years), the RAD framework helps explicitly consider whether or when the basin vision or goals may no longer be achievable, and direct options may open yet unconsidered potential for the basin. Embedding the RAD framework in hierarchical decision-making clarifies that the selection of actions in space and time should be derived from basin-wide goals and reach-scale objectives to ensure that site-scale actions contribute effectively to the larger river habitat mosaic. Embedding the RAD framework in large-river decisions can provide the necessary conduit to link flexibility and innovation at the site scale with stability at larger scales for adaptive governance of changing social-ecological systems.