As a typical geological structure, a soft interlayer is a key factor affecting the safety and stability of the entire slope. In order to better analyze the properties of soft interlayers and their influence on slope stability, the orthogonal control method was used to simulate four occurrence states of the sandwich depth, inclination angle, quantity and structural surface spacing between the layers of the slope with a soft interlayer in a mine open-pit rock slope. A 4×4 orthogonal simulation was carried out and the stability and deformation law of the slope were revealed under different occurrence states. The results show that: 1) the occurrence state of the soft and weak interlayer of the slope has a significant impact on the stability of the slope. The safety factor of the slope increases with the increase of the burial depth of the soft interlayer, and the safety factor tends to stabilize after the burial depth reaches a certain level. 2) With the increase in the angle of the soft interlayer, the failure mechanism is manifested as interlayer mismotion, creep slip along the layer and progressive change of shear-slip along the soft structural surface. 3) The increase in the number of soft interlayer layers leads to an overall decline in the slope with uneven deformation, a decrease in the safety factor of the slope, and an increase in horizontal displacement. 4) For the soft sandwich slope with the same buried depth, structural surface spacing has less influence on the slope safety factor when the spacing is small.