Landslide is a disastrous geological hazard in the Three Gorges Reservoir (TGR) area of China. In this study, random limit equilibrium analysis is conducted to assess a layered slope stability influenced by multi-factors in spatially variable soils, where the effects of earthquake, reservoir water level drawdown and rainfall are investigated, and possible failure modes and failure paths are identified. Furthermore, some sensitive analysis is performed to investigate the effects of the spatial variability of soil properties, water level drawdown velocity, rainfall intensity and pattern. Results show that the layered slope under complex working conditions exhibits the shallow failure modes, and the sliding surfaces are mainly located at the interface between soil layers. Meanwhile, the shear strength parameters in the shallow depth plays a crucial role in the layered slope failure probability. The earthquake has a prominent effect on slope stability, followed by reservoir water level drawdown and rainfall infiltration. The probability of failure under the combined effects of earthquake and other factors (e.g., 23.5%, 31.4% and 44.6%) is significantly higher than under the combined effects of rainfall and water level drawdown (e.g., 15.9%). Moreover, it can be found that the spatial variability of soil properties, water level drawdown velocity, rainfall intensity and pattern have essential impacts on the slope failure probability.