Persistence of many desert river species is threatened by a suite of impacts linked to water infrastructure projects that provide human water security where water is scarce. Many desert rivers have undergone regime shifts from spatially and temporally dynamic ecosystems to more stable systems dominated by homogenous physical habitat. Restoration of desert river systems could aid in biodiversity conservation, but poses formidable challenges due to multiple threats and the infeasibility of recovery to pre-development conditions. The challenges faced in restoring desert rivers can be addressed by incorporating scientific recommendations into restoration planning efforts at multiple stages, as demonstrated here through an example restoration project. In particular, use of a watershed-scale planning process can identify data gaps and irreversible constraints, which aid in developing achievable restoration goals and objectives. Site-prioritization focuses limited the resources for restoration on areas with the greatest potential to improve populations of target organisms. Investment in research to understand causes of degradation, coupled with adoption of a guiding vision is critical for identifying feasible restoration actions that can enhance river processes. Setting monitoring as a project goal, developing hypotheses for expected outcomes, and implementing restoration as an experimental design will facilitate adaptive management and learning from project implementation. Involvement of scientists and managers during all planning stages is critical for developing process-based restoration actions and an implementation plan to maximize learning. The planning process developed here provides a roadmap for use of scientific recommendations in future efforts to recover dynamic processes in imperiled riverine ecosystems.