jats:pUsing first principles modeling, we predict how substitutional doping can influence the mechanical strength of a Ag/ZnO interface commonly found in various multilayer thin-film systems. Replacing Zn with a monovalent dopant strengthens the interface while dopants with a valence greater than two weaken it. Isovalent dopants have little effect. The results are explained in terms of charge transfer and hybridization effects at the interface. Although monovalent dopants are mechanically preferred, they do not inhibit Ag inter-diffusion in ZnO and could possibly cause chemical degradation of the interface. It is suggested that other dopants, such as Bi, avoid this issue by creating larger diffusion barriers while maintaining a relatively strong interface. The results indicate that complete control over the mechanics, kinetics, and chemistry of the interface requires a careful choice of dopant types and concentrations.</jats:p>