Evaluation of slope stability under water level fluctuations is an important topic in the Three Gorges Reservoir (TGR) in China. However, most of the previous studies regarded slope soil as isotropic material, or only considered the influence of anisotropy ratio (kr = kx/ky) but ignored the anisotropy direction (α). Meanwhile, the pore pressure–stress coupling was rarely considered in the previous numerical simulations. In the present study, the SIGMA/W and SLOPE/W modules in Geo-studio are utilized to carry out the numerical simulation of Caipo slope under the drawdown of the reservoir water level, and the anisotropy ratio (kr) as well as the anisotropy direction (α) of two kinds of soils (clay and sand) are included. Results show that the anisotropy ratio kr and anisotropy direction α decrease the infiltration capacity of the soil, which increases the infiltration line hysteretic elevation (ILHE) as well as maximum horizontal displacement (MHD), and reduces the minimum safety factor (MSF). The slope toe firstly fails with the drawdown of water level. The influence of reservoir water level drop on seepage, deformation, and stability of the sand slope is less than that of the clay slope. For the sandy soil slope, it is not only necessary to consider the influence of kr, but also the influence of α. For the soil slope, we can only consider α in order to simplify calculation.