Youth suicide is increasing in the United States, with deaths among younger people of color driving this upward trend. For more than four decades, American Indian and Alaska Native (AIAN) communities have suffered disproportionate rates of youth suicide and years of productive life lost compared to other U.S. Races. The National Institute of Mental Health (NIMH) recently funded three regional Collaborative Hubs to carry out suicide prevention research, practice, and policy development with AIAN communities in Alaska and rural and urban areas of the Southwestern United States. The Hub partnerships are supporting a diverse array of tribally-driven studies, approaches, and policies with immediate value for increasing empirically driven public health strategies to address youth suicide. We discuss unique features of the cross-Hub work, including: (a) long-standing Community-Based Participatory Research processes that led to the Hubs’ innovative designs and novel approaches to suicide prevention and evaluation, (b) comprehensive ecological theoretical approaches that contextualize individual risk and protective factors in multilevel social contexts; (c) unique task-shifting and systems of care approaches to increase reach and impact on youth suicide in low-resource settings; and (d) prioritization of strengths-based approaches. The work of the Collaborative Hubs for AIAN youth suicide prevention is generating specific and substantive implications for practice, policy, and research presented in this article at a time when youth suicide prevention is a dire national priority. Approaches also have relevance for historically marginalized communities worldwide.