Heat transfer across the interfaces of dissimilar materials is a critical consideration in a wide variety of scientific and engineering applications. In this paper, molecular dynamics (MD) simulations are conducted to investigate the effects of thermal loading on mechanical properties of Al–Cu and Cr–Cu interfaces. The mechanical properties are investigated by MD simulations of nanoindentation. Both the results of MD simulations and experiments show the Young’s modulus decrease after thermal cycling, and the Cr–Cu interface is more sensitive to the thermal loading than the Al–Cu interface. The thermal loading and mechanical test models proposed here can be used to evaluate interfacial properties under the effects of heat transferring.