CaO-MgO-Al2O3-SiO2 (CMAS) penetration is an essential factor leading to the failure of thermal barrier coatings (TBCs), especially around the film-cooling hole structure of high-temperature gas turbine components. The complex temperature distribution and the free-edge effect around the cooling holes aggravate the influence of CMAS penetration on the failure of the TBCs. In this study, a three-dimensional (3D) model of a TBC-film cooling system considering CMAS attack is presented based on the observation of a retired turbine blade. CMAS penetration-induced change of thermo-mechanical properties of the ceramic top coat (TC) was considered. The thermal gradient around a cooling hole and the uneven growth of the thermally grown oxide (TGO) on the stress distribution in TBCs were investigated. The results showed that the thermal insulation performance of TBCs declined considerably under CMAS penetration, and the induced maximum increase in the temperature at the TC/bond coat (BC)interface reached 60 K. CMAS penetration also led to a considerable stress increase in the TBC-film system. We therefore conclude that CMAS penetration accelerates the crack initiation at the TC/TGO and TGO/BC interfaces.