Suicide and substance use disorders disproportionately affect American Indian and Alaska Native (AI/AN) Veterans, reflecting the intersecting impacts of historical trauma, colonization, military service–related stressors, and inequitable access to culturally responsive care. National surveillance data continue to show elevated suicide risk and unmet substance use treatment needs among AI/AN populations, with compounded vulnerability among Veterans navigating mainstream behavioral health systems. Despite sustained efforts, many Western evidence-based interventions have shown limited effectiveness when applied without attention to Indigenous worldviews, spiritual traditions, kinship systems, and community-defined pathways to healing. Historically, AI/AN Veterans have been excluded from the development of interventions intended to serve them, contributing to approaches that perpetuate stigma and cultural misalignment. This article presents an Indigenous-informed framework for substance use and mental health practitioners working with AI/ AN Veterans that integrates selected Western evidence-based practices with Indigenous practice-based evidence. The framework emphasizes relationality, spirituality, elder knowledge, cultural identity, and community accountability as core protective factors. Implications for culturally responsive clinical practice, training, and veteran-serving behavioral health systems are discussed.