The Endangered Species Act (ESA) continues to serve as one of the most powerful and contested federal legislative mandates for conservation. In the midst of heated debates, researchers, policy makers, and conservation practitioners champion the importance of cooperative conservation and social-ecological systems approaches, which forge partnerships at multiple levels and scales to address complex ecosystem challenges. However, few real-world examples exist to demonstrate how multifaceted collaborations among stakeholders who share a common goal of conserving at-risk species may be nested within a systems framework to achieve social and ecological goals. Here, we present a case study of Greater Sage-grouse (Centrocercus urophasianus) conservation efforts in the “Bi-State” region of California and Nevada, United States. Using key-informant interviews, we explored dimensions and drivers of this landscape-scale conservation effort. Three themes emerged from the interviews, including 1) ESA action was transformed into opportunity for system-wide conservation; 2) a diverse, locally based partnership anchored collaboration and engagement across multiple levels and scales; and 3) best-available science combined with local knowledge led to “certainty of effectiveness and implementation”—the criteria used by the US Fish and Wildlife Service to evaluate conservation efforts when making listing decisions. Ultimately, collaborative conservation through multistakeholder engagement at various levels and scales led to proactive planning and implementation of conservation measures and precluded the need for an ESA listing of the Bi-State population of Greater Sage-grouse. This article presents a potent example of how a systems approach integrating policy, management, and learning can be used to successfully overcome the conflict-laden and “wicked” challenges that surround at-risk species conservation.