Background: The environment affects children’s energy balance-related behaviors to a considerable extent. A context-based physical activity and nutrition school- and family-based intervention, named KEIGAAF, is being implemented in low socio-economic neighborhoods in Eindhoven, The Netherlands. The aim of this study was to investigate: 1) the effectiveness of the KEIGAAF intervention on BMI z-score, waist circumference, physical activity, sedentary behavior, nutrition behavior, and physical fitness of primary school children, and 2) the process related to the implementation of the intervention. Methods: A quasi-experimental, controlled study with eight intervention schools and three control schools was conducted. The KEIGAAF intervention consists of a combined top-down and bottom-up school intervention: a steering committee developed the general KEIGAAF principles (top-down), and in accordance with these principles, KEIGAAF working groups subsequently develop and implement the intervention in their local context (bottom-up). Parents are also invited to participate in a family-based parenting program, i.e., Triple P Lifestyle. Children aged 7 to 10 years old (grades 4 to 6 in the Netherlands) are included in the study. Effect evaluation data is collected at baseline, after one year, and after two years by using a child questionnaire, accelerometers, anthropometry, a physical fitness test, and a parent questionnaire. A mixed methods approach is applied for the process evaluation: quantitative (checklists, questionnaires) and qualitative methods (observations, interviews) are used. To analyze intervention effectiveness, multilevel regression analyses will be conducted. Content analyses will be conducted on the qualitative process data. Discussion: Two important environmental settings, the school environment and the family environment, are simultaneously targeted in the KEIGAAF intervention. The combined top-down and bottom-up approach is expected to make the intervention an effective and sustainable version of the Health Promoting Schools framework. An elaborate process evaluation will be conducted alongside an effect evaluation in which multiple data collection sources (both qualitative and quantitative) are used.