After large-scale and long-term waterflooding, reservoir physical properties such as the pore throat structure and rock wettability may change. In this paper, the relative permeability curves under different water injection volumes through core-flood experiments were used to characterize the comprehensive changes of various reservoir physical properties at high water-cut stage. The novel concept of "water cross-surface flux" was proposed to characterize the cumulative flushing effect on the reservoir by injected water, and a novel method for inverted five-spot reservoir simulation at high water-cut stage based on time-varying relative permeability curves was established. From the relative permeability curves measured through two cores from the X oilfield under different water injection volumes (100, 500, 1000, 1500, and 2000 PV), it is found that with the increase of injected water volume, the two-phase co-flow zone becomes wider, the water permeability under residual oil saturation increases, and the residual oil saturation decreases. A waterflooding core model was established, simulated, and verified by the method proposed in this paper. It is found that using time-varying permeability curves for simulation, the highest oil recovery factor (61.58%) can be obtained with injected water volume up to 2000 PV, and the purpose of improved oil recovery (IOR) can be achieved by high water injection volume, but the increment is only approximately 10%. Besides, a waterflooding model of an inverted five-spot reservoir unit based on the X oilfield was also established, simulated, and analyzed. Simulation results have shown that no matter which set of core permeability curves measured from 100 to 2000 PV is directly used alone, the oil recovery factor will be simulated inaccurately. The findings of this study can help in better understanding the quantitative description of the oil recovery changes with time-varying reservoir physical properties in high water-cut reservoirs during waterflooding.