Transition from the pediatric to the adult health care system is a complex process that should include medical, psychosocial, educational, recreational, and vocational considerations. In this systematic review, we aim to synthesize the evidence on transitional care interventions (TCIs) to improve the quality of life (QoL) for adolescents and young adults with childhood-onset disabilities, including neurodevelopmental disorders. Four electronic databases (Medline, Embase, PsycINFO, and Cumulative Index to Nursing and Allied Health Literature) were searched. In the included studies, researchers examined TCIs for adolescents and young adults (12-24 years of age) with childhood-onset disabilities. Studies were experimental, quasi-experimental, and observational studies published in the last 26 years. Two reviewers independently completed study screening, data extraction, and risk-of-bias assessment. Fifty-two studies were included. Five studies reported on QoL, but statistically significant improvements were noted in only 1 of these studies. Significant improvements were also found in secondary outcomes including disability-related knowledge and transitional readiness. TCIs targeted patients, families and/or caregivers, and health care providers and exhibited great heterogeneity in their characteristics and components. Inconsistent reporting on interventions between studies hindered synthesis of the relationships between specific intervention characteristics and outcomes. Although there is limited evidence on the impact of TCIs on the QoL for youth with childhood-onset disabilities, there is indication that they can be effective in improving patient and provider outcomes. The initiation of transition-focused care at an early age may contribute to improved long-term health outcomes in this population.