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Abstract Social-evaluative stressors—experiences in which people feel they could be judged negatively—pose a major threat to adolescent mental health 1–3 and can cause young people to disengage from stressful pursuits, resulting in missed opportunities to acquire valuable skills. Here we show that replicable benefits for the stress responses of adolescents can be achieved with a short (around 30-min), scalable 'synergistic mindsets' intervention. This intervention, which is a self-administered online training module, synergistically targets both growth mindsets 4 (the idea that intelligence can be developed) and stress-can-be-enhancing mindsets 5 (the idea that one’s physiological stress response can fuel optimal performance). In six double-blind, randomized, controlled experiments that were conducted with secondary and post-secondary students in the United States, the synergistic mindsets intervention improved stress-related cognitions (study 1, n  = 2,717; study 2, n  = 755), cardiovascular reactivity (study 3, n  = 160; study 4, n  = 200), daily cortisol levels (study 5, n  = 118 students, n  = 1,213 observations), psychological well-being (studies 4 and 5), academic success (study 5) and anxiety symptoms during the 2020 COVID-19 lockdowns (study 6, n  = 341). Heterogeneity analyses (studies 3, 5 and 6) and a four-cell experiment (study 4) showed that the benefits of the intervention depended on addressing both mindsets—growth and stress—synergistically. Confidence in these conclusions comes from a conservative, Bayesian machine-learning statistical method for detecting heterogeneous effects 6 . Thus, our research has identified a treatment for adolescent stress that could, in principle, be scaled nationally at low cost.