Non-equilibrium wall turbulence with mean-flow three-dimensionality is ubiquitous in geophysical and engineering flows. Under these conditions, turbulence may experience a counter-intuitive depletion of the turbulent stresses, which has important implications for modelling and control. Yet, current turbulence theories have been established mainly for statistically two-dimensional equilibrium flows and are unable to predict the reduction in the Reynolds stress magnitude. In the present work, we propose a multiscale model which explains the response of non-equilibrium wall-bounded turbulence under the imposition of three-dimensional strain. The analysis is performed via direct numerical simulation of transient three-dimensional turbulent channels subjected to a sudden lateral pressure gradient at friction Reynolds numbers up to 1,000. We show that the flow regimes and scaling properties of the Reynolds stress are consistent with a model comprising momentum-carrying eddies with sizes and time scales proportional to their distance to the wall. We further demonstrate that the reduction in Reynolds stress follows a spatially and temporally self-similar evolution caused by the relative horizontal displacement between the core of the momentum-carrying eddies and the flow layer underneath. Inspection of the flow energetics reveals that this mechanism is associated with lower levels of pressurestrain correlation which ultimately inhibits the generation of Reynolds stress. Finally, we assess the ability of the state-of-the-art wall-modelled large-eddy simulation to predict non-equilibrium, three-dimensional flows.