Background Many studies reported that copper, zinc and magnesium play important roles in the pathogenesis and development of neonatal hyperbilirubinemia. Exchange transfusion and intensive phototherapy are known two modalities of therapy for severe neonatal hyper bilirubinemia, but the effect of them on those trace elements is unknown. Materials and Methods Copper, Zinc and Magnesium serum levels were measured before and after treatment with intensive phototherapy and exchange transfusion in full term neonates with indirect hyperbilirubinemia admitted to neonatal intensive care unit (NICU) of Minia and Sohag University hospitals, Egypt, during 2014-2016 and comparison with normal healthy neonates was done. Results There were significant higher copper and magnesium and lower zinc serum levels in neonates with indirect hyperbilirubinemia than controls before and after intensive phototherapy. These levels were significantly changed after exchange transfusion to be comparable with controls. Significant positive correlations between the total bilirubin levels and hemoglobin, copper, and magnesium serum levels and significant negative correlations with serum zinc levels were present. There were no significant correlations between maternal and neonatal copper, zinc or magnesium serum levels. Conclusion Neonates with indirect hyperbilirubinemia had significant higher copper and magnesium and lower zinc serum levels than healthy neonates which were not related to their maternal serum levels. Intensive phototherapy had no effect on their levels while exchange transfusion changed these levels to be comparable with that of normal healthy neonates.