Nanoscale interfacial evolution in Cu–Al wire bonds during isothermal annealing from 175°C to 250°C was investigated by high resolution transmission electron microscopy (HRTEM). The native aluminum oxide film (∼5nm thick) of the Al pad migrates towards the Cu ball during annealing. The formation of intermetallic compounds (IMC) is controlled by Cu diffusion, where the kinetics obey a parabolic growth law until complete consumption of the Al pad. The activation energies to initiate crystallization of CuAl2 and Cu9Al4 are 60.66kJmol−1 and 75.61kJmol−1, respectively. During IMC development, Cu9Al4 emerges as a second layer and grows together with the initial CuAl2. When Al is completely consumed, CuAl2 transforms to Cu9Al4, which is the terminal product. Unlike the excessive void growth in Au–Al bonds, only a few voids nucleate in Cu–Al bonds after long-term annealing at high temperatures (e.g., 250°C for 25h), and their diameters are usually in the range of tens of nanometers. This is due to the lower oxidation rate and volumetric shrinkage of Cu–Al IMC compared with Au–Al IMC.