Background: Social network interventions targeted at children and adolescents can have a substantial effect on their health behaviors, including physical activity. However, designing successful social network interventions is a considerable research challenge. In this study, we rely on social network analysis and agent-based simulations to better understand and capitalize on the complex interplay of social networks and health behaviors. More specifically, we investigate criteria for selecting influence agents that can be expected to produce the most successful social network health interventions. Objective: The aim of this study was to test which selection criterion to determine influence agents in a social network intervention resulted in the biggest increase in physical activity in the social network. To test the differences among the selection criteria, a computational model was used to simulate different social network interventions and observe the intervention’s effect on the physical activity of primary and secondary school children within their school classes. As a next step, this study relied on the outcomes of the simulated interventions to investigate whether social network interventions are more effective in some classes than others based on network characteristics. Methods: We used a previously validated agent-based model to understand how physical activity spreads in social networks and who was influencing the spread of behavior. From the observed data of 460 participants collected in 26 school classes, we simulated multiple social network interventions with different selection criteria for the influence agents (ie, in-degree centrality, betweenness centrality, closeness centrality, and random influence agents) and a control condition (ie, no intervention). Subsequently, we investigated whether the detected variation of an intervention’s success within school classes could be explained by structural characteristics of the social networks (ie, network density and network centralization). Results: The 1-year simulations showed that social network interventions were more effective compared with the control condition (beta=.30; t100=3.23; P=.001). In addition, the social network interventions that used a measure of centrality to select influence agents outperformed the random influence agent intervention (beta=.46; t100=3.86; P<.001). Also, the closeness centrality condition outperformed the betweenness centrality condition (beta=.59; t100=2.02; P=.046). The anticipated interaction effects of the network characteristics were not observed. Conclusions: Social network intervention can be considered as a viable and promising intervention method to promote physical activity. We demonstrated the usefulness of applying social network analysis and agent-based modeling as part of the social network interventions’ design process. We emphasize the importance of selecting the most successful influence agents and provide a better understanding of the role of network characteristics on the effectiveness of social network interventions.