Background and Objectives: Hydroxyurea (HU) is an effective medication used to reduce the frequency of painful crises associated with sickle cell disease (SCD). However, data describing its prevalence among SCD patients in the Eastern Region of Saudi Arabia are scarce. This is a multi-center, retrospective, cross-sectional study that aims to investigate the pattern of prescribing HU in SCD patients and to determine the association between prescribing HU and other co-prescribed medications used to manage SCD complications. Methods: Data were collected from patients who visited the hematology clinics of Al-Qatif Central Hospital (QCH) and King Fahad Hospital in Hofuf (KFHH) between June 2021 to May 2023. The data included demographics, prescribed medications, and recent laboratory test results, all of which were collected from patients’ medical records. Descriptive statistics were utilized to assess the difference between HU users vs. non-users. A binary logistic regression model was used to determine the association between prescribing HU and co-prescribed medications used to manage SCD complications. The results are presented as the odds ratio (OR) and 95% confidence interval (95% CI). Results: This study included 2816 SCD patients with a 56% prevalence of HU prescription. HU was prescribed for young age groups more often compared to old age group patients. Young males were more likely to be prescribed with HU compared to females, and it becomes dominant in females after the age of 36. HU users were more likely to have paracetamol (69% vs. 53%, OR = 1.9, 95% CI 1.6–2.2), NSAIDs (50% vs. 35%, OR = 1.7, 95% CI 1.5–2), and opioids (41% vs. 37%, OR = 1.3, 95% CI 1.1–1.6) co-prescribed, and less often to have laxatives (8% vs. 5%, OR = 0.66, 95% CI 0.48–0.9) and anticoagulants (22% vs. 15%, OR = 0.56, 95% CI 0.46–0.68) co-prescribed compared to non-users. Conclusions: The pattern of prescribing HU, supported by the association findings, raises concerns about patients’ compliance and adherence to HU therapy. Early health education, specifically to young female SCD patients, is warranted to increase the success rate of HU therapy.