Background: Chronic red cell transfusion (CRCT) therapy is one of a few effective disease-modifying therapies for children with sickle cell anemia (SCA). CRCT is recommended for primary and secondary stroke prevention for at-risk children with SCA and is sometimes used for other disease-related complications. However, CRCT can be resource- and time-intensive for patients/families, providers, and organizations. This study was conducted to provide a comprehensive, multilevel examination of barriers and facilitators to transfusion therapy in children with SCA from health care provider and caregiver perspectives. Methods: A qualitative descriptive approach was used to conduct key informant interviews in a sample of 26 caregivers and 25 providers across the United States. Interviews were analyzed using directed content analysis with the Multilevel Ecological Model of Health as an initial coding framework and the constant comparison method. Results: Ten barrier themes and 10 facilitator themes emerged across all ecological levels. Themes most commonly occurred on the patient and organizational levels. Key barriers themes included Logistical Challenges, Obtaining and Maintaining Venous Access, Alloantibodies/Alloimmunization and Reactions, and Iron Overload and Adherence to Chelation Therapy. Key facilitator themes included Nursing and Non-nursing Staff Support, Positive Child/Family Experiences, Logistical Help and Social Resources, Blood Bank and Access to Blood, and Transfusion-Specific Resources. Discussion: The comprehensive understanding of multilevel barriers and facilitators to transfusion therapy, including the role of nursing, in children with SCA can inform strategies to improve CRCT for patients/families and providers and can also be applied by organizations seeking to implement transfusion services for SCA.