With the increase of operating temperature of aero-engine turbine blades, a vitreous material (CMAS) consisting mainly of CaO, MgO, Al2O3 and SiO2 are increasingly harmful to the thermal barrier coatings deposited on the blade. Therefore, the performance and durability of thermal barrier coatings should be improved. The influence of CMAS penetration on interfacial crack propagation and residual stress in the thermal barrier coatings prepared by electron beam physical vapor deposition was investigated by the finite element method. The sinusoidal curves with fixed wavelength and varying amplitude were used to model the interfaces with different roughness. At the same time, the effect of the elastic modulus of CMAS and the interaction between interface and CMAS were taken into account. The results show that the increase of CMAS elastic modulus has an inhibitory effect on interfacial cracks, and that the smaller the thermally grown oxide (TGO) amplitude and thickness, the more obvious the inhibition. There is a critical point for CMAS elastic modulus to affect the maximum residual stress S-22 in top coat (TC) layer. Before the critical point, the change of CMAS elastic modulus has a greater influence on the maximum residual stress of TC layer, and with the increase of elastic modulus of CMAS, the maximum residual stress of TC layer decreases greatly; after the critical point, the maximum residual stress of TC layer is hardly affected by the change of elastic modulus of CMAS. These results are of great significance to study the failure mechanism of thermal barrier coatings prepared by electron beam physical vapor deposition, and can provide guidance for the optimization of the interface of thermal barrier coatings.