School-based programs can effectively prevent substance use; however, systematic reviews and consultation with stakeholders identified a need for effective, culturally inclusive programs for Aboriginal and/or Torres Strait Islander (hereafter Aboriginal) youth. This paper describes the development of Strong & Deadly Futures, a six-lesson, curriculum-aligned wellbeing and substance use prevention program that was designed for, and with, the Aboriginal youth. Formative reviews and consultation recommended that the program (i) combine effective components of mainstream prevention with cultural elements, highlighting Aboriginal cultural strengths; (ii) avoid stigma and celebrates the cultural diversity by catering to both Aboriginal and non-Aboriginal students; and (iii) use digital technology to enhance engagement, implementation and scalability. Guided by an Appreciative Inquiry approach, the program was developed in partnership with an Indigenous Creative Design Agency, and four schools in New South Wales and Queensland, Australia. Aboriginal (n = 41) and non-Aboriginal students (n = 36) described their role models, positive aspects of their community and reasons to avoid substance use; these formed the basis of an illustrated story which conveyed the key learning outcomes. Feedback from teachers, students and content experts supported the acceptability of the program, which will be evaluated in a subsequent randomised controlled trial.