In the middle and late period of many oil and gas fields, reservoir depletion occurred usually resulting in pressure depletion of shale cap, which had an effect on wellbore stability in the drilling process. According to the elastic mechanics theory of porous media, and making the indoor test, the influences on cap strength and in-situ stress of pressure depletion were studied, and taking them into the mechanical analysis of wellbore stability. Using the related formation parameters of shale cap in some structure, the influence rule on cap collapse and fracture pressure of reservoir depletion were studied. The results showed that, the collapse and fracture pressure of shale cap was both reduced due to reservoir depletion, the cap leakage risk increased, and it is the main prevention object.