<p>The opioid epidemic greatly impacts adolescents, especially those with low perceived risk of harm—an important predictor of misuse initiation. Here, to address this, we developed and evaluated PlaySmart, a videogame targeting perceived risk, in a two-arm parallel superiority unblinded randomized controlled trial with a placebo comparator. We randomized 532 participants (mean age 16.6 years; 47% female) to PlaySmart (<i>n</i> = 269) or control games (<i>n</i> = 263). Eligible students—16–19 years old, no prior opioid misuse and ‘high-risk’ based on substance use or mental health screens—agreed to 60-min gameplay sessions, and provided assent and parental consent if under 18 years old. Participants played during supervised after-school sessions (1 or 2 times per week for approximately 6 weeks) at 15 Connecticut high schools. Self-reported data were collected at baseline, 6 weeks and 3 months (21 October 2021 to 27 February 2024). Follow-up rates were high (231/266 (87%) PlaySmart and 234/261 (90%) control). The primary outcome was perceived risk of harm of opioid misuse at 3 months. The secondary outcomes were self-efficacy, intentions, knowledge and attitudes (positive and negative expectancies). At 3 months, 29% of PlaySmart versus 23% of control participants reported ‘great risk’ with no statistically significant difference between groups (95% CI, –2% to 14%; <i>P</i> = 0.14). Self-efficacy, intentions and positive expectancies did not differ. PlaySmart participants demonstrated knowledge gains from baseline to 3 months (2.1 (95% CI, 1.4–2.7) versus 0.1 (95% CI, –0.6–0.7); <i>P</i> &lt; 0.001), and negative expectancies gains at 6 weeks (2.3 (95% CI, 1.4–3.1) versus 0.2 (95% CI, –0.7–1.1); <i>P</i> = 0.001). Further research is needed to enhance PlaySmart, maximizing its impact on scalable opioid misuse prevention.</p><p>ClinicalTrials.gov registration: NCT04941950.</p>