The microstructure evolution of heteroepitaxial BaTiO3 (BTO) thin films grown on single crystal (001) SrTiO3 (STO) under Ne irradiation at room temperature was systematically investigated with special attention given to the behavior at the BTO/STO interface. Cross sectional transmission electron microscope investigations reveal that amorphization occurs at the top BTO film region. BTO grains in the dimensions of 10–20 nm survived the irradiation damage and maintained their original crystal orientation. Other irradiation-induced defects such as dislocation loops and defect clusters were observed only at the portion of the BTO thin film near the interface, but not at the STO side of the bilayer. Atomic calculations find that the energetics of defects are very similar on each side of the BTO/STO interface, suggesting that the interface will not significantly modify radiation damage evolution in this system, in agreement with the experimental observations. These results support the hypothesis we presented in previous work about the role of coherent interfaces on radiation damage evolution.