A pressure gradient increase from normal pressure in oil zones to overpressure in dry gas zones indicates a lateral disequilibrium of pore pressure in many shale reservoirs. In this work, conditions for the preservation of the lateral pressure disequilibrium during uplift and erosion are investigated. Numerical simulations were conducted by coupling pressure–volume–temperature (PVT) and fluid dynamic calculations. Results show that temperature decrease and pore volume expansion during erosion tends to increase the pressure gradient in the gas or condensate zone and tends to decrease the pressure gradient in the black oil zone; therefore, the PVT effect tends to enhance lateral pressure disequilibrium during erosion. Low permeability is crucial for the preservation of the lateral pressure disequilibrium. The persistence of disequilibrium over geological time (tens of millions of years) requires extremely small vertical permeability (sub-picodarcy range) and horizontal permeability (10 nd or even lower). The horizontal permeability is 10–100 times smaller than laboratory measurements on shale plugs, indicating a discontinuity of laminations and fractures within a shale formation.