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Background: Hydroxyurea (HU) is a disease‐modifying therapy with significant clinical and laboratory efficacy among individuals living with sickle cell anaemia (SCA). This is evident through increased fetal haemoglobin, higher packed cell volume, improved red cell hydration, reduced leukocytes, and platelet function. The effect on the coagulation pathway and pathophysiologic mechanism remains unclear, especially in children living with SCA. This study evaluated the coagulation profile using D‐dimer and thrombin antithrombin complex (TAT) in children with SCA. Methods: The cross‐sectional study was conducted over three months at LUTH among 80 children living with SCA in steady state aged 2–18 years (40 HU exposed and 40 HU naïve, respectively). Blood samples were assayed for D‐dimer, TAT, and complete blood count. Descriptive analysis such as mean and standard deviation for normally distributed variables or median and interquartile range for skewed data were used to summarize continuous variables, while proportion or percentages for categorical variables. Univariate analysis and bivariate analysis were done and statistical significance was set at p < 0.05. Results: The mean age (±SD) of study participants in both groups was 11.35 (±4.6 years). D‐dimer levels (23.27 ng/mL) and TAT (29.79 pg/mL) were significantly lower among HU exposed compared to HU naïve children (62.73 ng/mL and 109.34 pg/mL, respectively) p < 0.001. There was a negative correlation between D‐dimer and TAT with the duration of HU use (r = −0.499, p = 0.001, and r = −0.401, p = 0.010), respectively. There was a positive correlation between D‐dimer and TAT with total WBC (r = 0.368, p = 0.019, and r = 0.385, p = 0.014, respectively) among the HU naïve participants and a negative correlation between D‐dimer and TAT with haemoglobin level (r = −0.303, p = 0.047, and r = −0.311, p = 0.041, respectively) among HU exposed children. Conclusion: HU modulates the D‐dimer and TAT levels of children living with SCA toward the normal reference range, thus reducing the risk of hypercoagulability and associated sequelae. Therefore, continuous advocacy for HU use should entail close monitoring of adverse effects. [ABSTRACT FROM AUTHOR]