Maintaining wellbore stability involves significant challenges when drilling in low-permeability reactive shale formations. In the present study, a non-linear thermo-chemo-poroelastic model is provided to investigate the effect of chemical, thermal, and hydraulic gradients on pore pressure and stress distributions near the wellbores. The analysis indicates that when the solute concentration of the drilling mud is higher than that of the formation fluid, the pore pressure and the effective radial and tangential stresses decrease, and v. v. Cooling of the lower salinity formation decreases the pore pressure, radial and tangential stresses. Hole enlargement is the combined effect of shear and tensile failure when drilling in high-temperature shale formations. The shear and tensile damage indexes reveal that hole enlargement occurs in the vicinity of the wellbore at an early stage of drilling. This study also demonstrates that shale wellbore stability exhibits a time-delay effect due to changes in the pore pressure and stress. The delay time computed with consideration of the strength degradation is far less than that without strength degradation.