Sickle cell disease (SCD) is still one of the highest leading inbred hemoglobinopathy amid Africans. The In-vitro effects of hesperidin on sickling human erythrocytes with functional chemistry of human sickle erythrocytes were investigated by standard methods.The induction of sickle cell in erythrocytes was done using 2%sodium metabisulphite at 3 hours optimally. The prevention and curative approaches (PA and CA) were adopted in comparison of human erythrocytesfrom AA-genotype. The erythrocytes were grouped into 3; AA–hesperidin treated (AA××), AA–hesperidin treated (AA×) and sickle cell serving as negative control (NC). The results showed 83% and 86% antisickling potency of hesperidin for prevention and curative approaches respectively. The results of functional chemistry analysis showed that hesperidin modifies the functional groups in favor of its antisickling effects judging from the FTIR observed bends and shifts. From GC-MS and LC-MS analyses, it was practical that hesperidin treatment favors the productions of fatty acid alkyl monoesters (FAMEs) with concomitant shutting down-effects on selenocompound metabolism. Pathway enrichment and topology analyses revealed non-specifically activation of fatty acid biosynthesis, linoleic acid metabolism and steroid hormone biosynthesis pathways upon hesperidin treatment. Thus, sickling-suppressive effects of hesperidin could potentially be associated with modulation of oxygenated and deoxygenated haemglobinthroughpossible modification of human sickle erythrocyte’s functional chemistry.