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Summary Sickle cell anaemia (SCA) is a debilitating genetic haemoglobinopathy predominantly affecting the disenfranchised strata of society in Africa and the Americas. The most common pharmacological treatment for this disease is the administration of hydroxycarbamide (HC) for which questions remain regarding its mechanism of action, efficacy and long‐term toxicity specifically in paediatric individuals. A multiplatform metabolomics approach was used to assess the metabolome of plasma samples from a population of children and adolescents with SCA with and without HC treatment along with non‐SCA individuals. Fifty‐three metabolites were identified by ultra‐high performance liquid chromatography coupled to high‐resolution mass spectrometry (UHPLC‐HRMS) and 1H nuclear magnetic resonance (NMR) with a predominance of membrane lipids, amino acids and organic acids. The partial least‐squares discriminant analysis (PLS‐DA) analysis allowed a clear discrimination between the different studied groups, revealing clear effects of the HC treatment in the patients’ metabolome including rescue of specific metabolites to control levels. Increased creatine/creatinine levels under HC treatment suggests a possible increase in the arginine pool and increased NO synthesis, supporting existing models for HC action in SCA. The metabolomics results extend the current knowledge on the models for SCA pathophysiology including impairment of Lands’ cycle and increased synthesis of sphingosine 1‐phosphate. Putative novel biomarkers are suggested.

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