Due to the rapid increase in current density encountered in new chips, the phenomena of thermomigration and electromigration in the solder bump become a serious reliability issue. Currently, Ni or TiN, as a barrier layer, is widely academically studied and industrially accepted to inhibit rapid copper diffusion in interconnect structures. Unfortunately, these barrier layers are polycrystalline and provide inadequate protection because grain boundaries may presumably serve as fast diffusion paths for copper and could react to form Cu–Sn intermetallic compounds (IMCs). Amorphous metallic films, however, have the potential to be the most effective barrier layer for Cu metallization due to the absence of grain boundaries and immiscibility with copper. In this article, the diffusion properties, the strength of the interface between polycrystalline and amorphous ZrCuNiAl thin film, and the effects of quenching rate on the internal microstructures of amorphous metal films were individually investigated by molecular dynamics (MD) simulation. Moreover, experimental data of the diffusion process for three different cases, i.e., without barrier layer, with an Ni barrier layer, and with a Zr53Cu30Ni9Al8 thin film metallic glass (TFMG) barrier layer, were individually depicted. The simulation results show that, for ZrCuNiAl alloy, more than 99% of the amorphous phase at a quenching rate between 0.25 K/ps and 25 K/ps can be obtained, indicating that this alloy has superior glass-forming ability. The simulation of diffusion behavior indicated that a higher amorphous ratio resulted in better barrier performance. Moreover, a very small and uniformly distributed strain appears in the ZrCuNiAl layer in the simulation of the interfacial tension test; however, almost all the voids are initiated and propagated in the Cu layer. These phenomena indicate that the strength of the ZrCuNiAl/Cu interface and ZrCuNiAl layer is greater than polycrystalline Cu. Experimental results show that the Zr53Cu30Ni9Al8 TFMG layer exhibits a superior barrier effect. Almost no IMCs appear in this TFMG barrier layer even after aging at 125 °C for 500 h.