Interfacial failure under thermal cycling conditions is one of the main concerns in package design. To minimize such failure in multi-layered electronic assemblies and packages, it is important to develop a better understanding of the reliability at a molecular level. In this paper, molecular dynamics (MD) simulations were conducted to investigate the interfacial energy of the epoxy molding compound (EMC) cuprous oxide system during the thermal cycling test. In order to investigate the effect of the cuprous oxide content in the copper substrate on the interfacial adhesion, two kinds of MD models were examined in this study. The results revealed that the cuprous oxide content in the copper substrate had a large effect on the interfacial adhesion between the EMC and copper, which is consistent with the experimental observation.