Colorado Pikeminnow Ptychocheilus lucius, the Colorado River’s top native predatory fish, was historically distributed from the Gulf of California delta to the upper reaches of the Green, Colorado, and San Juan rivers in the Colorado River basin in the Southwestern US. In recent decades Colorado Pikeminnow population abundance has declined, primarily due to predation by warmwater nonnative fish and habitat modification following dam construction. Small, reproducing populations remain in the Green and upper Colorado rivers, but their current population trajectory is declining and the San Juan River population is maintained primarily through stocking. As such, establishment of an additional population could aid recovery efforts and increase the species’ resilience and population redundancy. The Colorado River in Grand Canyon once supported Colorado Pikeminnow, but until recently habitat suitability in this altered reach was considered low due to a depressed thermal regime and abundant nonnative predators. Climate change and ongoing drought has presented an opportunity to evaluate the feasibility of native fish restoration in a system where declining reservoir storage has led to warmer releases and re-emergence of riverine habitat. These changes in the physical attributes of the river have occurred in concert with a system-wide decline in nonnative predators. Conditions ten years ago were not compatible with reintroduction feasibility in Grand Canyon; however, due to rapidly changing conditions an expert Science Panel was convened to evaluate whether the physical and biological attributes of this reach could now support various life stages of Colorado Pikeminnow. Here, we report on the evaluation process and outcome from the Science Panel, which developed a science-based recommendation to the U.S. Fish and Wildlife Service on reintroduction feasibility. The Science Panel concluded that current habitat attributes in Grand Canyon could satisfy some, but perhaps not all, Colorado Pikeminnow life history requirements. This reach has the potential to support adult and sub-adult growth, foraging, migrations, and spawning, but low juvenile survival may limit recruitment. However, populations of other native species are successfully reproducing and increasing in western Grand Canyon, even in areas once considered suboptimal habitat. Should managers decide to move to the next phase of this process, actions such as experimental stocking and monitoring, telemetry studies, bioenergetics modeling, and laboratory-based research may provide additional information to further evaluate a potential reintroduction effort in this rapidly changing but highly altered system.