As anthropogenic influences push ecosystems past tipping points and into new regimes, complex management decisions are complicated by rapid ecosystem changes that may be difficult to reverse. For managers who grapple with how to manage ecosystems under novel conditions and heightened uncertainty, advancing our understanding of regime shifts is paramount. As part of an ecological resilience assessment, researchers and managers have collaborated to identify alternate regimes and build an understanding of the thresholds and factors that govern regime shifts in the Upper Mississippi River System. To describe the management implications of our assessment, we integrate our findings with a recently developed framework that explicitly acknowledges ecosystem regime change and outlines management approaches of resisting change, accepting change, or directing change. More specifically, we developed guidance for using knowledge of desirability of current conditions, distance to thresholds, and general resilience (that is, an ecosystem’s capacity to cope with uncertain disturbances) to navigate the resist-accept-direct (RAD) framework. We applied this guidance to outline strategies that resist, accept, or direct change in the context of management of aquatic vegetation, floodplain vegetation, and fish communities across nearly 2000 river kilometers. We provide a case study for how knowledge of ecological dynamics can aid in assessing which management approach(es) are likely to be most ecologically feasible in a changing world. Continued learning from management decisions will be critical to advance our understanding of how ecosystems respond and inform the management of ecosystems for desirable and resilient outcomes.