BACKGROUND: Accurate childhood cancer survival estimates are crucial for policy makers and clinicians for priority-setting and planning decisions. However, observed survival estimates are lacking for many countries, and when available, wide variation in outcomes is reported. Understanding the barriers to optimising survival can help improve childhood cancer outcomes. We aimed to provide estimates of global childhood cancer survival, accounting for the impact of multiple factors that affect cancer outcomes in children. METHODS: We developed a microsimulation model to simulate childhood cancer survival for 200 countries and territories worldwide, accounting for clinical and epidemiologic factors, including country-specific treatment variables, such as availability of chemotherapy, radiation, and surgery. To ensure model results were consistent with reported survival data, we calibrated the model to estimates from the CONCORD-2 and CONCORD-3 studies using an Approximate Bayesian Computation approach. We estimated 5-year net survival for diagnosed cases of childhood cancer in each country and territory and estimated potential survival gains of seven policy interventions focused on improving treatment availability and delivery (ie, increasing the availability of chemotherapy, radiation, general surgery, neurosurgery, or ophthalmic surgery, reducing treatment abandonment, and improving the quality of care to the mean of high-income countries) implemented in isolation or as packages. FINDINGS: Our model estimated that, for diagnosed cases, global 5-year net childhood cancer survival is currently 37·4% (95% uncertainty interval 34·7-39·8), with large variation by region, ranging from 8·1% (4·4-13·7) in eastern Africa to 83·0% (81·6-84·4) in North America. Among the seven policy interventions modelled, each individually provided small gains, increasing global 5-year net survival to between 38·4% (35·8-40·9) and 44·6% (41·7-47·4). 5-year net survival increased more substantially when policy interventions were bundled into packages that improved service delivery (5-year net survival 50·2% [47·3-53·0]) or that expanded treatment access (54·1% [50·1-58·5]). A comprehensive systems approach consisting of all policy interventions yielded superadditive gains with a global 5-year net survival of 53·6% (51·5-55·6) at 50% scale-up and 80·8% (79·5-82·1) at full implementation. INTERPRETATION: Childhood cancer survival varies widely by region, with especially poor survival in Africa. Although expanding access to treatment (chemotherapy, radiation, and surgery) and addressing financial toxicity are essential, investments that improve the quality of care, at both the health-system and facility level, are needed to improve childhood cancer outcomes globally. FUNDING: Boston Children's Hospital, Dana-Farber Cancer Institute, Harvard TH Chan School of Public Health, Harvard Medical School, National Cancer Institute, SickKids, St Jude Children's Research Hospital, Union for International Cancer Control, Children with Cancer UK Davidson and O'Gorman Fellowship.