Management and conservation efforts that support the recovery and protection of large rivers are daunting, reflecting the complexity of the challenge and extent of effort (in terms of policy, economic investment, and spatial extent) needed to afford measurable change. These large systems have generally experienced intensive development and regulation, compromising their capacity to respond to disturbances such as climate change or wildfire. Functionally, large river and basin management require insights gained from social, ecological, geophysical, and hydrological sciences. This multi-disciplinary perspective can unveil the integrated relationship between a river network's biotic community and seasonally variable environmental conditions that are often influenced by human activities. Large rivers and their basins are constantly changing due to anthropogenic influences and as climate modifies patterns of temperature and precipitation. Because of these factors, the state of knowledge must advance to address changing conditions. The Willamette River, in western Oregon, USA, is a prime example of a basin that has experienced significant degradation and investment in rehabilitation in recent decades. Innovative science has facilitated development of fine-scale, spatially extensive datasets and models that can generate targeted conservation and rehabilitation actions that are prioritized across the entire river network. This prioritization allows investment decisions to be driven by site-specific conditions while simultaneously considering potentials for ecological improvement. Here, we review hydrologic, geomorphic, ecologic, and social conditions in the Willamette River basin through time—including pre-settlement, river development, and contemporary periods—and offer a future vision for consideration. Currently, detailed information about fish populations and habitat, hydrologic conditions, geomorphology, water quality, and land use can be leveraged to make informed decisions about protection, rehabilitation, and development. The time is ripe for strategic management and goal development for the entire Willamette River, and these efforts can be informed by comprehensive science realized through established institutions (e.g., public agencies, non-profit watershed groups, Tribes, and universities) focused on conservation and management. The approaches to science and social-network creation that were pioneered in the Willamette River basin offer insights into the development of comprehensive conservation-based planning that could be implemented in other large river systems globally.