Limited research exists on the relationship between changes in physical activity levels and injury in children. In this study, we investigated the prognostic relationship between changes in activity, measured by the acute:chronic workload ratio (ACWR), and injury in children. We used data from the Childhood Health, Activity, and Motor Performance School Study Denmark (2008-2014), a prospective cohort study of 1,660 children aged 6-17 years. We modeled the relationship between the uncoupled 5-week ACWR and injury, defined as patient-reported musculoskeletal pain, using generalized additive mixed models. These methods accounted for repeated measures, and they improved model fit and precision compared with previous studies that used logistic models. The prognostic model predicted an injury risk of approximately 3% between decreases in activity level of up to 60% and increases of up to 30%. Predicted risk was lower when activity decreased by more than 60% (minimum of 0.5% with no recreational activity). Predicted risk was higher when activity increased by more than 30% (4.5% with a 3-fold increase in activity). Girls were at significantly higher risk of injury than boys. We observed similar patterns but lower absolute risks when we restricted the outcome to clinician-diagnosed injury. Predicted increases in injury risk with increasing activity were much lower than those of previous studies carried out in adults.