Sickle cell disease (SCD) can significantly impair the health-related quality of life (HRQOL) of children and adolescents. This review aimed to assess current evidence regarding the HRQOL of children and adolescents with SCD in the Middle East and North Africa region. A systematic search of various databases was conducted to identify relevant articles, including MEDLINE® (National Library of Medicine, Bethesda, Maryland, USA), Scopus® (Elsevier, Amsterdam, the Netherlands), Cumulative Index to Nursing and Allied Health Literature®, Masader (Oman Virtual Science Library, Muscat, Oman) and EBSCOhost (EBSCO Information Services, Ipswich, Massachusetts, USA). A total of 533 articles were identified; however, only 10 were eligible for inclusion in the final analysis. Results from these studies showed that children and adolescents with SCD had compromised HRQOL compared to their healthy peers, particularly in terms of physical, psychosocial, familial, financial and academic functioning. Therefore, interventions are necessary to improve overall HRQOL outcomes for this population.