This review aims to explore the impact of sickle cell disease (SCD) on patients' quality of life (QoL) and the effectiveness of different transfusion modalities, particularly automated red blood cell exchange (aRBCX), in managing the factors that impact QoL. A systematic search was performed in PubMed to retrieve articles with data on QoL in SCD patients treated with aRBCX during the last 20 years. A targeted search for medical guidelines and a free search were added. When assessing the impact of the transfusion modality on the QoL of patients with SCD, some studies indicated an improvement in health-related QoL when using aRBCX while others reported no differences. The benefits of aRBCX include a decrease in length of hospital stay, pain-related hospitalizations and procedure time. The drawbacks of aRBCX were also identified, including an increased number of procedure-related complications (despite the overall number of complications showing no significant differences) and a more complex vascular access. Chronic red blood cell exchange favours psychosocial factors such as anxiety and social functioning, but the impact of using aRBCX in these parameters is not determined yet. aRBCX, known to be an efficient procedure to manage SCD, appears to be promising in improving patients' QoL. However, more comprehensive studies incorporating patient-reported outcomes are needed to fully understand the impact of different transfusion modalities on QoL in SCD patients. An integrated care approach, including psychological support and pain management, may further enhance QoL.