The penetration of calcium-magnesium-alumino-silicate (CMAS) is one of the most vital factors inducing the failure of air plasma sprayed thermal barrier coatings (APS TBCs). The CMAS penetration into the porous microstructures of TBCs changes the thermal/mechanical properties of top coat (TC) material, this brings about considerable thermal mismatch stress at the TC/bond coat (BC) interface, and accelerates the growth of the thermally grown oxide (TGO), finally leading to more complicated stress state at the interface. In present study, a two-dimensional global model of APS TBCs with half of the TC penetrated by CMAS is built to study effect of non-uniform CMAS penetration. Then, a local model extracted from the global are built to investigate the effect of interface morphologies and CMAS penetration depth. The results showed that non-uniform CMAS penetration in APS TBCs causes non-uniform TGO growth, which further leads to more complicated interface stress distribution. The CMAS penetration depth had a greater effect on the TC/TGO interface stress behavior, while the interface roughness had an more obvious influence on the stress level at BC/TGO interface under CMAS penetration.