BackgroundThere are no available school-based alcohol and drug prevention programs with evidence of effectiveness among Aboriginal and Torres Strait Islander youth. To address this, we codeveloped the Strong & Deadly Futures well-being and alcohol and drug prevention program in partnership with an Indigenous creative design agency and 4 Australian schools.ObjectiveThis paper presents the protocol to evaluate the effectiveness of Strong & Deadly Futures in reducing alcohol and other drug use and improving well-being among Aboriginal and Torres Strait Islander youth.MethodsThe target sample will be 960 year 7 and 8 students from 24 secondary schools in Australia, of which approximately 40% (384/960) will identify as Aboriginal or Torres Strait Islander. The study design is a 2-group, parallel cluster randomized controlled trial with allocation concealment. Recruited schools will be block randomized (ratio 1:1), stratified by geographical remoteness, by an independent statistician. Schools will be randomized to receive Strong & Deadly Futures, a web-based alcohol and drug prevention and social and emotional well-being program that delivers curriculum-aligned content over 6 lessons via an illustrated story, or health education as usual (control). Control schools will be supported to implement Strong & Deadly Futures following trial completion. Surveys will be administered at baseline, 6 weeks, 12 months, and 24 months (primary end point) post baseline. Primary outcomes are alcohol use (adapted from the National Drug Strategy Household Survey), tobacco use (Standard High School Youth Risk Behavior Survey), and psychological distress (Kessler-5 Psychological Distress Scale). Secondary outcomes are alcohol and drug knowledge and intentions, alcohol-related harms, binge drinking, cannabis use, well-being, empowerment, appreciation of cultural diversity, and truancy.ResultsThe trial was funded by the National Health and Medical Research Council in January 2019, approved by the Human Research Ethics Committee of the University of Sydney (2020/039, April 2020), the Aboriginal Health and Medical Research Council of New South Wales (1620/19, February 2020), the Western Australian Aboriginal Health Ethics Committee (998, October 2021), and the ethics committees of each participating school, including the New South Wales Department of Education (2020170, June 2020), Catholic Education Western Australia (RP2020/39, November 2020), and the Queensland Department of Education (550/27/2390, August 2021). Projected dates of data collection are 2022-2024, and we expect to publish the results in 2025. A total of 24 schools have been recruited as of submission of the manuscript.ConclusionsThis will be the first cluster randomized controlled trial of a culturally inclusive, school-based alcohol and drug prevention program for Aboriginal and Torres Strait Islander youth; therefore, it has significant potential to address alcohol and other drug harms among Aboriginal and Torres Strait Islander youth.Trial RegistrationAustralian New Zealand Clinical Trials Registry ACTRN12620001038987; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=380038&isReview=trueInternational Registered Report Identifier (IRRID)PRR1-10.2196/34530