A thermomechanical coupling model of ultrasonic welding with an interlayer of Cu nanoparticles (NPs) was established using the ANSYS software. The specific heat and thermal conductivity of Cu NPs and the effect on the friction coefficient of Cu/Cu contact surface were considered in the model. The effect of the thermal softening and ultrasonic softening on the yield strength of the material was also considered. The accuracy of the model was verified by comparing the experimental results of the welding interface temperature and the weld cross section shape with the corresponding simulation results. The simulation results showed the distribution and change of weld temperature and plastic strain under different welding time, which were in good agreement with the experimental result. In addition, the stress of the joint during lap shear testing is simulated by finite element method.