BACKGROUND: Physical activity and structural differences in the hippocampus have been linked to educational outcome. We investigated whether a curriculum-based physical activity intervention correlates positively with children’s academic achievement, psychological well-being, health-related quality of life (HRQoL), fitness, and structural development of the brain. METHODS: The study had a quasi-experimental design and a control group. National test results were gathered from 545 students, 122 in the intervention school, and 423 in 3 control schools. HRQoL and socioemotional data were collected with child and proxy versions of KIDSCREEN and the Strength and Difficulties Questionnaire. Overall, 79 students in grades 5 and 6 were recruited for an in-depth study, consisting of a submaximal oxygen consumption test and magnetic resonance imaging of the brain. HRQoL and socioemotional data were collected from 349 students (65%), 182 (52%) in the intervention school, and 167 (48%) in one of the control schools. RESULTS: Girls attending the intervention school were more likely to pass national tests in Swedish (odds ratio 5.7) and Mathematics (odds ratio 3.2). The fourth to sixth graders in the intervention school reported lower levels of conduct problems (p < .05), and the girls were also less likely to report hyperactivity (p < .05). Girls reported higher levels of emotional problems (p < .05) than boys. Boys in the intervention group had significantly higher levels of estimated maximal oxygen uptake (p < .05) than controls. No difference in hippocampal structure was seen. CONCLUSIONS: Curriculum-based physical activity in school may improve the academic achievement and psychological health of children, particularly for girls.