Indigenous communities demonstrate immense cultural strengths despite being impacted by mental health and academic disparities due to ongoing systemic racism and historical trauma. Given that schools are a context in which indigenous youths’ needs have potential to be met through preventive intervention, this scoping review explores and summarizes the cultural relevance of school-based prevention interventions that have been implemented with students from indigenous backgrounds. We included articles published between January 2010 and February 2021 that included descriptive, outcome, and/or program development data on school-based prevention programs used with indigenous students in the USA and Canada. The initial search yielded 2131 articles for review, and ultimately 35 articles describing 27 interventions were included in the final sample. The majority of the programs (n = 20) were focused on substance use prevention or sexual and reproductive health and targeted adolescents in middle and high school; only five programs focused on mental health, social-emotional learning, and academics. All interventions were culturally consonant, but the program development process differed: 11 interventions were culturally grounded (i.e., developed based on values and beliefs of a specific cultural group) with one being community initiated (i.e., grassroots development), and 17 were culturally adapted (i.e., the tailoring of an existing intervention for a specific cultural group). We describe each intervention and its cultural components and provide commentary on how school-based prevention and social-emotional learning interventions can promote academic success for indigenous students in the USA and Canada.