Mental health and substance use are pressing public health concerns among Indigenous adolescent populations. This systematic review analyzed interventions focusing on mental health and substance use that utilize the Positive Youth Development (PYD) framework, incorporate culturally tailored programs, and are geared toward Indigenous adolescents. In total, 474 articles were retrieved from PSYCInfo and PubMed databases. Eight articles were eligible for analysis, with six focusing on AI/AN populations in the U.S. Most programs reported positive or expected outcomes. All the programs incorporated PYD variables, while all but one were culturally grounded or included deep structure adaptations. Implications are further discussed.