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Background: Hydroxyurea (HU) is the first disease-modifying drug used in the treatment of sickle cell disease (SCD). Despite its well-documented benefits, adoption and drug adherence have remained difficult. Aim: This study focused on determining the uptake rate of HU among SCD patients and the effects of HU on the disease outcome. Methodology: This was a retrospective hospital-based study conducted in four Nigerian tertiary institutions from October 2016 to September 2021. Data on their basic demographics, steady-state hematologic parameters, acute and chronic SCD-related events, and the use of HU were retrieved and analysed using the Statistical Package for the Social Sciences (SPSS) version 21. Statistics were both descriptive and inferential. Results: Of 509 SCD patients’ data analysed, 251 were male (49.3%), while 258 were female (50.7%). Their mean age was 26.9 (standard deviation ± 8.11) years; range: 18–63 years. Only 28 (5.5%) of the 509 patients were receiving or had ever received HU therapy. The steady-state hematological variables between individuals who are on hydroxyurea and those who are not hydroxyurea showed a statistically significant difference. Individuals who experience priapism (21.4%) and stroke (10.7%) were considerably more likely to be on HU (P = 0.001, 0.043), whereas patients not on HU were more likely to experience pulmonary hypertension (2.5%) (P = 0.001). Conclusion: The uptake of HU among SCD patients was low. Further prospective studies are encouraged to ascertain the factors responsible for this. There is a need for improved patients’ education and counselling to increase the level of awareness of HU and its benefits among patients.