High-intensity focused ultrasound (HIFU) has been confirmed to be useful for cancer treatment. However, the miniaturization of traditional impedance matching networks for HIFU has limitations. In this paper, a time-division multiplex auto-impedance matching network is proposed for Class D power amplifiers used in HIFU systems to improve performance and reduce the system size. A comparison with previous articles shows that the proposed system can automatically compensate for the impedance drifting of five-channel transducers caused by temperature variations or manufacture tolerance. The operating frequency of the circuit is 1.25 MHz, and the power consumption is 416 mW.