Due to the dissimilarities in the hydration characteristics and degree of clay minerals, the wellbore instability and sloughing of deep shale is more sudden and destructive than that of the shallow shale. Previous works mainly consider the effects of temperature and pressure condition on the wellbore instability of deep shale at macroscopic scale, and ignore the microscopic mechanism of strength weakening during hydration and the evolution characteristics of montmorillonite(MMT) hydration under different isomorphic substitutions, temperature and pressure conditions. By considering the characteristics of clay minerals and drilling fluids in deep shales, the molecular dynamics simulations of MMT hydration in deep shale under different isomorphic substitutions, water content, temperature and pressure conditions were carried out to analyze the distribution and conduction evolution characteristics of water molecules and cations, and the response characteristics of crystal elastic parameters during the hydration process. The results indicate that: (1) As the water content increases, the interlayer spacing increases, but it is less sensitive to the temperature and pressure. Moreover, with the increase of water content, water molecules and ions are accelerated to intrude into crystal layer, and the hydration effects are enhanced and the weakening effects on rock strength are increased as well. (2) Both temperature and pressure have significant influences on the hydration characteristics of MMT, but the influential trends are opposite. Increasing temperature promotes the invasion of water molecules and sodium ions into the crystal layer so as to enhance the hydration, the weakening effect on rock strength becomes more remarkable. On the contrary, with the increase of pressure, the diffusion coefficient of water molecules and sodium ions to interlayer decreases which inhibits the weakening effect of clay hydration. (3) The differences of hydration characteristics of MMT with typical isomorphic substitutions are significant. The hydration ability of sodium ion in Fe-substituted MMT was weaker and the diffusion coefficient of water molecules was larger, so that water molecules more easily invade into the crystal layer, and the strength weakening is more significant than that of the Mg-substituted MMT system. Furthermore, the weakening effect is more significant under high temperature and low pressure conditions. The microscopic dynamic mechanism of clay hydration in deep shale can be throughly understood through molecular dynamics simulation, which provides an innovative research approach for the quantitative evaluation of drilling fluid hydration inhibition and microscopic control of clay hydration in deep shale.