In order to analyze the thermal problem from ultrasonic cavitations in the low-frequency sonophoresis process for transdermal drug delivery, this paper establishes a stimulation model for piezoelectric-sound-thermal coupling fields in sonophoresis based on COMSOL Multiphysics software, which utilizes piezoelectric, heat transfer and acoustic balance equations. Further, the temperature field distribution and maximum surface temperature curve changing with time are acquired from both the finite element method (FEM) and thermal imaging system with input electrical power of 5.5 W and driving frequency of 21 kHz. The simulation and calculation results show that the temperature field distribution and maximum surface temperature curve of the FEM calculations are consistent with those of the experimental results in both the alone-heating ultrasonic transducer and low-frequency sonophoresis system with a Franz diffusion cell in the air. In the low-frequency sonophoresis process, sharp sound attenuation caused by ultrasonic cavitations in the liquid contributes to fast heating, due to the transformation of acoustic energy into thermal energy. In the thermal imaging experiments, the highest surface temperature in the sonophoresis system reached 40℃ in 15 min. According to the simulation results, the maximum temperature of the whole system reached 41.3℃, which meets the temperature safety requirements of 42℃ or lower for low-frequency sonophoresis transdermal drug delivery. Calculated and experimental results demonstrate that by predicting the temperature distribution, the piezoelectric-acoustic-thermal coupling calculation model is beneficial for the design of ultrasonic radiation time control, the determination of structure size, and the optimization of the material parameters of the ultrasonic transducer, and thereby lays a theoretical basis for the multiple applications of different sonophoresis conditions.