Adolescent opioid misuse, addiction, and overdose have emerged as national health crises. Nearly 17% of high school students have misused prescription opioids. The purpose of this study was to evaluate the reach and acceptability of a widelyused prescription opioid misuse prevention program, This Is (Not) About Drugs© (TINAD), and its preliminary efficacy at improving opioid misuse knowledge, opioid misuse attitudes, self-efficacy to avoid opioid misuse, and intentions to misuse opioids. Participants were 576 7th grade students (M age = 11.8; 51% boys; 39% Hispanic, 31% White, 20% Black) from a rural county in the southeastern U.S. All participants received the TINAD program and completed pretest and immediate posttest assessments. The program was school-based and implemented in collaboration with school teachers and administrators. Over 91% of all eligible students in the school district participated in the TINAD program. Most participants found the program acceptable-over 83% of students liked the program. Approximately 9% of participants reported prior misuse of prescription opioids. After participating in TINAD, students self-reported higher knowledge and self-efficacy as well as safer attitudes. However, there was no change in intentions to misuse opioids in the future. Effects of the program were consistent across gender, socioeconomic status, race/ethnicity, and previous opioid misuse. TINAD is acceptable and shows promise for improving opioid-related cognitions. However, more rigorous experimental and longitudinal research is needed to understand whether TINAD reduces opioid misuse over time. Given the limited research on adolescent opioid misuse prevention, this study lays the ground work for future randomized control trials.