Background The adolescent and young adult (AYA) period is a time of high morbidity and mortality for persons with sickle cell disease (SCD). The goal of this study was to use implementation science combined with qualitative methods to understand the determinants of an optimal transition to adult care for AYA with SCD. Methods Sixty participants were purposefully recruited from a large hospital system and the community for 16 focus groups or semi-structured interviews. Patient-caregiver dyads and health care providers shared experiences in the health care and academic settings. Data were coded and analyzed by paired coders using an inductive coding approach in combination with an implementation research framework, the Consolidated Framework for Implementation Research (CFIR). Results At the Individual Characteristics level, AYA patients expressed challenges with adult life experiences, disease self-management, and preparation for the adult health care model. Caregivers and health care providers reported independence and autonomy as facilitators of a successful transition. At the Inner and Outer Setting levels, differences between pediatric and adult health care models were noted barriers, highlighting the gap in patient-centered care. Patient and provider communication was identified as both a barrier and facilitator. A standardized approach to transition planning and coordination was noted as a facilitator. At the Intervention Characteristics level, adaptability, incentive, and perceived attractiveness of the intervention were important components. Conclusion This study highlights which determinants of transition are most amenable to evidence-based interventions. This is imperative for rapidly improving this process for AYA with SCD and, thus, improving overall outcomes.