To measure the incidence of vaso-occlusive crises (VOC) and the role of hydroxyurea (HU) in reducing VOC in sickle cell anemia patients being treated at a large tertiary care setting in Kingdom of Saudi Arabia (KSA). The secondary objective of this study is to observe the gradual improvement in laboratory data (white blood cell [WBC], platelets, mean corpuscular volume [MCV], hemoglobin [Hgb], HgbF) following regular use of HU. Methods: Clinical effectiveness of HU was evaluated in a large pediatric population using a retrospective cohort, non-interventional, pre-post treatment study designed to control disease severity selection bias. The cohort included children with SCA (sickle cell (SS), sickle-beta thalassemia) at King Saud Medical City, Riyadh, KSA, who initiated HU between January 2012 and June 2017. For each patient healthcare utilization, laboratory values, and clinical outcomes were observed for an equal duration of time pre and post hydroxyurea. Results: Out of 416 SCD patients, 128 children with SCD who initiated HU, of them 82 met the eligibility criteria. After initiation of HU, there was significant reduction in both VOC (80%) and length of stay (LOS) (73%). Significant increase in Hgb (13%), MCV (10%), and HgbF (28%) and significant decrease in WBC (28%) was observed. Only the mean platelet count decreased by 3% with a p greater than 0.05. Conclusion: Hydroxyurea treatment significantly decreased episodes of VOC and LOS, it also led to reductions in hospitalizations and significant improvement in complete blood count indices.