Sickle cell disease (SCD) affects two-thirds of African and Indian children. Understanding the molecular mechanisms contributing to oxidative stress may be useful for therapeutic development in SCD. We evaluated plasma elemental levels of Indian SCD patients, trait and healthy controls (n=10/per group) via ICP-MS. Additionally, erythrocyte metabolomics of Indian SCD and healthy (n=5/per group) was carried out using LC-MS mass-spectrometry. Followed by assessment of antioxidant defence enzymes namely glutathione reductase (GR), superoxide dismutase (SOD), and catalase (CAT) in erythrocytes and plasma of Indian SCD patients (n=31) compared to trait (n=8) and healthy (n=9). In SCD plasma an elevated plasma 24Mg, 44Ca, 66Zn, 208Pb, 39K and reduced 57Fe, 77Se, 85Rb levels indicating higher hemolysis and anemia. Erythrocyte metabolome of SCD patients clustered separately from heathy revealing 135 significantly deregulated metabolic features including trimethyllysine, pyroglutamate, glutathione, aminolevulinate, and D-glutamine indicating oxidative stress and membrane fragility. Repressed GR, SOD, and CAT activities were observed in SCD patients of which GR and CAT activities did not change under hypoxia. These findings lead to the hypothesis that SCD-associated metabolic deregulations and a shift to ATP-consuming aberrant γ-glutamyl cycle leads to anemia, dehydration, oxidative stress and hemolysis driving the biomechanical pathophysiology of erythrocyte of SCD patients.