Sickle cell anemia (SCA) is a hereditary condition that can lead to severe complications in children such as acute coronary syndrome, splenic sequestration, renal failure, and stroke. Blood transfusion and hydroxyurea (HU) therapy are used to prevent stroke in children with sickle cell disease (SCD). Preliminary data show considerable variation and inconsistency in the use of these two therapeutic interventions. Therefore, this systematic review was carried out to compare the effects of blood transfusion to HU therapy in preventing stroke for children with sickle cell disease. There was an extensive literature search in reliable and authentic databases like PubMed, Medline, Scopus, Cochrane, and Science Direct to obtain relevant articles. This study used the standards and guidelines from the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). During the systematic review, data were obtained focusing on the following parameters: the size of the sample in the study, the age of the subjects involved in the study, the type of Intervention, and the outcome. After an initial search of 163 papers, 25 studies were included. The results of the research give the first evidence that HU is effective in the treatment of cerebrovascular problems in children with SCD. However, it is unclear under what circumstances HU may prevent a second stroke. It can be concluded that children with SCA can effectively avoid primary strokes through chronic blood transfusions and HU.