We examine gravity-driven two-layer flow of generalized Newtonian fluids. The two layers have different densities and constitutive laws, and the flow is assumed to be shallow and inertia-less. A depth-integrated model for flow over one-dimensional topography is derived with the volume fluxes written in terms of functions that depend only on the fluids’ rheology. The model enables two-layer flows of any combination of generalized Newtonian fluids to be computed without explicit knowledge of the velocity profile. For viscoplastic layers, the formulation provides a convenient way to determine the layer evolution without having to analyse the multiple yield surfaces that may occur. Motivated by the lubricated flow of ice sheets, we analyse the case in which the lower layer is relatively thin. The model reduces to a one-layer flow with an effective slip law that encapsulates the thickness and generalized Newtonian rheology of the lower layer. For flow over two-dimensional topography, a depth-integrated two-layer model cannot generally be derived because the direction of the shear stress varies across the lower layer. Progress is possible in the special cases that the lower layer is Newtonian or is relatively thin.