Objective: Although survival rates in childhood cancer have improved, prevention and reduction of late effects remain important. This study evaluates the effects of a combined physical exercise and psychosocial intervention on health-related quality of life (HrQoL) and psychosocial functioning in childhood cancer patients. Methods: In this multicenter randomized controlled trial, cancer patients (aged 8–18 years) and their parents filled in questionnaires on HrQoL, depressive symptoms, behavioral problems, and self-esteem. Measurements were conducted at baseline, shortly after the 12-week intervention period and 12 months after baseline. Generalized estimating equations analyses were performed to assess short-term and long-term psychosocial effects. Results: Of the 174 eligible patients, 68 (39.1%) participated. The intervention group consisted of 30 participants at baseline [mean age 13.0 (SD 3.0) years; 53% male], 26 at short-term and 22 at long-term follow-up. The ‘care as usual’ control group consisted of 38 participants at baseline [mean age 12.6 (SD 3.1) years; 53% male], 33 at short-term and 31 at long-term follow-up. Overall, the intervention did not improve psychosocial functioning and HrQoL. According to parent-proxy reports, the intervention leads to a greater improvement on pain-related HrQoL on both the short (β = 13.4; 95% CI: 3.0; 23.8) and long term (β = 13.0; 95% CI: 1.6; 24.4) and to greater improvement on procedural anxiety immediately after the intervention (β = 12.6; 95% CI: 1.9; 23.3). Conclusion: A combined physical and psychosocial training for children with cancer did not have effects on HrQoL or psychosocial functioning, with exception of modest positive effects on parent-reported pain and procedural anxiety.