Participation in recommended levels of physical activity promotes a healthy body weight and reduced chronic disease risk. To inform investment in prevention initiatives, we simulate the national implementation, impact on physical activity and childhood obesity and associated cost-effectiveness (versus the status quo) of six recommended strategies that can be applied throughout childhood to increase physical activity in US school, afterschool and childcare settings. In 2016, the Childhood Obesity Intervention Cost Effectiveness Study (CHOICES) systematic review process identified six interventions for study. A microsimulation model estimated intervention outcomes 2015–2025 including changes in mean MET-hours/day, intervention reach and cost per person, cost per MET-hour change, ten-year net costs to society and cases of childhood obesity prevented. First year reach of the interventions ranged from 90,000 youth attending a Healthy Afterschool Program to 31.3 million youth reached by Active School Day policies. Mean MET-hour/day/person increases ranged from 0.05 MET-hour/day/person for Active PE and Healthy Afterschool to 1.29 MET-hour/day/person for the implementation of New Afterschool Programs. Cost per MET-hour change ranged from cost saving to $3.14. Approximately 2500 to 110,000 cases of children with obesity could be prevented depending on the intervention implemented. All of the six interventions are estimated to increase physical activity levels among children and adolescents in the US population and prevent cases of childhood obesity. Results do not include other impacts of increased physical activity, including cognitive and behavioral effects. Decision-makers can use these methods to inform prioritization of physical activity promotion and obesity prevention on policy agendas.