Melatonin is a pineal gland hormone that has a potent antioxidant characteristic. The presence of an extra copy of SOD on chromosome 21 in Down syndrome (DS) patients' was corelated with free radicals generations that affect several internal organs. This study aims to correlate the effect of DS dependent oxidative stress on melatonin expression and liver and thyroid gland functions. Blood plasma of twenty young children DS patients' and ten healthy controls were collected and tested for the levels of SOD, H₂O₂, melatonin, Liver functions enzymes, total proteins, TSH, T3 and T4 using colorimetric and ELISA techniques. SOD overexpression leads to H₂O₂ accumulation and melatonin downregulation which in turn leads to a status of oxidative stress affecting Liver functions indicated by total protein significant downregulation. A direct impact of oxidative stress and melatonin downregulation was corelated to DS -dependent hypothyroidism of significant TSH upregulation and T3 andT4 downregulation. In conclusion, the reduction at melatonin endogenous levels in plasma of young children DS patients' may highlight its role in upsurge the DS-dependent oxidative stress invulnerable pathological features. This study recommends the implication of melatonin in prospective clinical trials of DS therapy.