The stability, reactivity and functionality of modern nanostructured and nanoarchitectured materials, like nano-multilayers (NMLs) and nanocomposites (NCs), are generally ruled by fast short-circuit diffusion of atoms along internal interfaces, such as phase and grain boundaries (GBs), at relatively low temperatures. Residual stresses can have a significant effect on the kinetics of short-circuit diffusion in these nanomaterials, which has been largely neglected up to date. We present a combined experimental-modelling approach for deriving stress-free activation energies (and related diffusion coefficients) for the grain boundary diffusion of a given element across an inert barrier nanolayer, which can be utilized to perform fundamental investigations and model predictions of GB diffusion kinetics across inert barrier nanolayers in the presence of a varying stress field. The method was applied to investigate the diffusion of Cu along W grain boundaries in Cu/W nano-multilayers in the temperature range from 400 °C to 600 °C. Firstly, the GB diffusion kinetics as function of the temperature and stress state were determined from experiment by combining in situ heating AES analysis and ex situ XRD stress analysis. The experimental data were compared to model predictions from a modified Hwang–Balluffi model, which accounts for a varying stress level within the barrier during the annealing. The extracted stress-free activation energy for grain boundary diffusion of Cu in W (~0.29 eV) is substantially lower than the respective experimental value for a high compressive stress within the W barrier nanolayer. The corresponding stress-free Cu GB diffusion coefficient in W equals D_b* = (3.2 ± 0.6) x 10^-15exp(-0.29 ± 0.02eV/kT) cm²/s.