Stress is a widespread phenomenon and young people especially are experiencing high levels of stress. School-related factors are the most frequently self-reported stressors among adolescents, but few interventions have targeted the school environment. This study evaluated the effectiveness of the Healthy High School (HHS) intervention on stress at a 9-month follow-up. The study included 5201 first-year high school students (~16 years) in Denmark. Participating schools were randomized into the HHS intervention (N = 15) or control group (N = 15). Baseline measurements were conducted in August 2016 and the follow-up was conducted in May 2017. The intervention was designed to promote well-being (primary outcome) by focusing on physical activity, meals, sleep, sense of security, and stress (secondary outcomes). The intervention comprised: structural initiatives at the school level; a teaching material; peer-led innovation workshops; and a smartphone app. The 10-item Perceived Stress Scale was used to measure stress. Intervention effects on perceived stress were estimated using an intention-to-treat approach with multiple imputations of missing data and multilevel general linear regression modelling. A total of 4577 students answered the baseline questionnaire. No statistically significant difference was found in stress between students at intervention and control schools at the follow-up (mean score: 16.7 versus 16.7, adjusted b = 0.42, 95% CI: −0.16;1.00). The HHS Study is one of the first large randomized controlled trials targeting school environmental stressors. Potential implementation failures and the failures of the program theory are discussed.