Purpose: ¡Activate Ya! was a group-randomized controlled intervention trial aimed at developing and evaluating the impact of a school-based intervention on preventing cigarette smoking and promoting physical activity (PA) in secondary school students in Uruguay. Secondary aims were to evaluate the program’s impact on students’ smoking- and PA-related psychosocial risk and protective factors. Methods: Sixteen schools and n = 654 students participated in the study. The one-year intervention included a classroom-based curriculum, an afterschool program, activity breaks, and final showcase event. A self-administered questionnaire measured outcomes at three time points. Fixed effects regression models tested for differences in outcomes by study condition. Results: While positive intervention effects were found for selected psychosocial-related smoking outcomes, no impact on past-year smoking or smoking susceptibility was detected. Past 7-day PA, measured by the PAQ-C, was significantly higher among intervention school students overall ( p = .048) and for girls ( p = .03) at posttest, and intervention girls reported significantly higher athletic identity PA competence, friend and teacher PA support at posttest, and PA enjoyment at follow-up ( p < .05). Conclusion: The positive short-term effects of ¡Activate Ya! on PA and related outcomes for girls support the utility of school-based health promotion in Uruguay. Additional research is needed to determine the most effective strategies to prevent tobacco use among students and promote PA among boys in this setting.