Background: A considerable proportion of contemporary youth have a high risk of obesity-related disorders such as cardiovascular disease, metabolic syndrome, or non-alcoholic fatty liver disease (NAFLD). Although there is consistent evidence for the positive effects of physical activity on several health aspects, most adolescents in Colombia are sedentary. It is, therefore, important to implement strategies that generate changes in lifestyle. The HEPAFIT study aims to examine whether a 6-month exercise program has benefits for hepatic fat content and cardiovascular health outcomes among overweight/obese adolescents from Bogotá, Colombia. Methods/design: Altogether, 100 hundred overweight/obese, sedentary adolescents (aged 11-17 years) attending two public schools in Bogotá, Colombia, will be included in a parallel-group randomized controlled trial. Adolescents will be randomly assigned to an intervention group following one of four curricula: (1) the standard physical education curriculum (60 min per week of physical activity, n = 25) at low-to-moderate intensity; (2) a high-intensity physical education curriculum (HIPE, n = 25), consisting of endurance and resistance games and non-competitive activities, such as running, gymkhanas, lifting, pushing, wrestling, or hauling, for 60-min sessions, three times per week, with an energy expenditure goal of 300 to 500 kcal/session at 75-85% maximum heart rate (HRmax); (3) a low-to-moderate intensity physical education curriculum (LIPE, n = 25) consisting of endurance and resistance games and non-competitive activities (e.g., chasing, sprinting, dribbling, or hopping) for 60-min sessions, three times per week with an energy expenditure goal of 300 kcal/session at 55-75% HRmax; and (4) a combined HIPE and LIPE curriculum (n = 25). The HIPE, LIPE, and combined interventions were performed in addition to the standard physical education curriculum. The primary outcome for effectiveness is liver fat content, as measured by the controlled attenuation parameter 1 week after the end of the intervention program. Discussion: The translational focus may be suitable for collecting new information in a school setting on the possible effects of physical activity interventions to reduce liver fat content and to improve metabolic profiles and the cardiometabolic health of overweight/obese adolescents. This may lead to the more efficient use of school physical education resources.