Tumor microvascular damage caused by the alternate cooling and heating treatment was found much more severe than that of cooling or heating alone from our previous experimental studies. The induced stresses on the vessel wall are expected to play an important role in vascular damage. Both thermal and mechanical stresses are involved due to the rapid changes in temperature and blood reperfusion during the treatment. To investigate the stress effect, theoretical modeling and numerical simulations have been performed in the present study. Thermal stresses on the tumor microvessel wall during the freezing process are analyzed using the elastic models through the coupled field method. To simulate mechanical stresses induced by blood reperfusion, the fluid and structural mechanics are coupled on the interface between the blood flow domain and the vessel wall. Numerical results show that the thermal stress on the vessel wall is negative in the tumor center, indicating the compression effect during the freezing process. The magnitude of the radial stress reaches . During the postheating process, the nonuniform stress distribution exists in the tortuous periphery vessel wall owing to the irregular structures, and higher stresses normally appear at the vessel bifurcations. Synergy of the thermal and mechanical stresses on the vessel wall play critical roles in damaging of the heterogeneous tumor vasculature during the alternate cooling and heating treatment. Results obtained in the present study are expected to help better understand the vascular injury process, and to develop a more effective thermal treatment protocol for tumor therapy.