Abstract Background Disparities in sexually transmitted infections (STI) are an urgent problem among Native American youth and young adults which are not fully explained by different sexual or related behaviors. These sexual health disparities are more likely attributed to social environments and structural determinants such as a shortage of sexual healthcare providers, lower socioeconomic status, and access barriers to STI screening and treatment, including geographic isolation and confidentiality concerns. Innovative, non-clinic based alternatives to promote STI screening and treatment are essential for alleviating these disparities. Self-care, or the care taken by individuals towards their own health and well-being may be such a strategy. This study will assess the efficacy of a self-care intervention, called Protecting Our Future Generation, for increasing uptake of STI screening and impacting sexual risk and protective behaviors among Native American youth and young adults living in a reservation-based community in the Southwestern United States. Methods The proposed study is a randomized controlled trial to test the efficacy of a self-care intervention compared to a control condition. Participants will be Native Americans ages 14–26 years old who have had vaginal or anal sex at least once in their lifetime. Participants will be randomized to the intervention which includes: 1) a sexual health self-assessment with embedded clinical prediction tool predicting STI positivity, and 2) personalized messaging with key steps to lower risk for STIs, or the control condition which includes: 1) a self-assessment about water, soda and sugar sweetened beverage consumption, and 2) personalized messaging to meet recommended daily intake. All participants will be offered a self-administered STI test. Participants will complete assessments at baseline, 3- and 6-months follow-up. The primary outcome measure is completion of STI screening. Discussion Protecting Our Future Generation is among the first self-care interventions uniquely focused on sexual health among a Native American population, who endure significant sexual health disparities and are under-represented in research. If efficacious, the intervention will be a model of sexual health self-care for Native American youth and young adults adaptable for use in healthcare and community-based settings. Trial registration Clinical Trials: http://clinicaltrials.gov; NCT03895320; Registered 03/28/2019.