Sickle cell disease (SCD), a prevalent inherited non-communicable disease, remains a neglected public health priority, especially children and adolescents in many low- and middle-income countries. The global burden of SCD in youth remains under-characterized given fragmented data and disparities in diagnostics. This study aims to conduct a systematic review and meta-analysis quantifying the global prevalence and cause-specific mortality of SCD in individuals aged under-5 and under-20. A search was conducted to identify studies reporting SCD prevalence or mortality published between 2017 and 2023. Eligible studies were assessed for quality and random-effects meta-analyses generated pooled estimates, stratified by age group, study design and United Nations country group classification. Fifty-seven studies were included, encompassing data from over 3.6 million individuals and 56 593 recorded deaths. Among children under-5, the prevalence was 0.008 (95% confidence interval [CI]: 0.004-0.016). The global under-20 population-based prevalence of SCD was 0.009 (95% CI: 0.005-0.017). The global under-20 cause-specific mortality proportion was 0.029 (95% CI: 0.001-0.621), with under-5 and 5-19 years of age mortality proportions estimated at 0.021 and 0.017, respectively. This first global synthesis of under-5s and under-20s demonstrates substantial paediatric burden but is constrained by extreme heterogeneity, wide uncertainty and incomplete geographic coverage, underscoring the urgency for improved screening, surveillance and cause-of-death attribution to support accurate global burden estimation of SCD.